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Deuruxolitinib

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Deuruxolitinib

C17H18N6, 314.422

Fda approved Leqselvi, 7/25/2024, To treat severe alopecia areata

C-21543, CTP 543, CTP-543, CTP543

(3r)-3-(2,2,3,3,4,4,5,5-d8)cyclopentyl-3-(4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-1h-pyrazol-1-yl)propanenitrile

1h-pyrazole-1-propanenitrile, .beta.-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-, (.beta.r)-D8-ruxolitinib

IngredientUNIICASInChI Key
Deuruxolitinib phosphate8VJ43S4LCM2147706-60-1JFMWPOCYMYGEDM-NTVOUFPTSA-N

unii
0CA0VSF91Y

Deuruxolitinib, sold under the brand name Leqselvi, is a medication used for the treatment of alopecia areata.[1] It is a Janus kinase inhibitor selective for JAK1 and JAK2.[2] Although the relative effectiveness of deuruxolitinib and another Janus kinase inhibitor—baricitinib—for alopecia areata may vary depending on the population studied, both drugs are more effective than alternative treatments.[3]

Deuruxolitinib was approved for medical use in the United States in July 2024.[1][4]

Medical uses

Deuruxolitinib is indicated for the treatment of adults with severe alopecia areata.[1]

Side effects

The FDA prescribing label for deuruxolitinib contains a boxed warning for serious infections; malignancies; cardiovascular death, myocardial infarction, and stroke; and thrombosis.[5]

Society and culture

Names

Deuruxolitinib is the international nonproprietary name[6] and the United States Adopted Name.[7]

SYN

20240108633METHOD FOR PREVENTING OR TREATING DISEASE OR CONDITION ASSOCIATED WITH ANTITUMOR AGENT

20240058345TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS

2023553253重水素化JAK阻害剤による脱毛障害の治療のためのレジメン

20230390292REGIMENS FOR THE TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS

20230322787PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS

1020230093504중수소화된 JAK 억제제를 이용한 탈모 장애의 치료를 위한 요법

WO/2023/018954TREATMENT OF JAK-INHIBITION-RESPONSIVE DISORDERS WITH PRODRUGS OF JAK INHIBITORS

2022171838TREATMENT OF ALOPECIA CAUSED BY DEUTERATED JAK INHIBITOR

2022171838TREATMENT OF ALOPECIA CAUSED BY DEUTERATED JAK INHIBITOR

20220226327Combination therapy comprising JAK pathway inhibitor and rock inhibitor

20220213105PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS

20220202834JAK inhibitor with a vitamin D analog for treatment of skin diseases

20210387991Deuterated JAK inhibitor and uses thereof SUN

WO/2020/163653PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS CONCERT

20200222408TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS

2019516684Treatment of Hair Loss Disorders with Deuterated JAK Inhibitors

PATENT

US20210387991

USE OF COMPD NOT SYNTHESIS

https://patentscope.wipo.int/search/en/detail.jsf?docId=US344953814&_cid=P12-M0XGHQ-19840-2

Example 1

Synthesis of Compound 10

      The synthesis of Compound 10, or a pharmaceutically acceptable salt thereof (such as the phosphate salt) may be readily achieved, e.g., reaction of CTP-543 under conditions suitable to provide hydrolysis of the nitrile functionality of CTP-543. CTP-543 can be prepared, e.g., according to the methods described in U.S. Pat. No. 9,249,149 and US Patent Pub. No. 2019/0160068 (the teachings of which are incorporated herein by reference), to produce CTP-543 and/or its phosphate salt. CTP-543 phosphate salt may be transformed into Compound 10 or its phosphate salt according to Scheme 1 below.
      
      To a round bottom flask, equipped with a magnetic stir bar, was charged sulfuric acid (2 mL) followed by careful addition of CTP-543 Phosphate (4.05 g, 9.8 mmol). To the mixture was added another portion of sulfuric acid (2 mL) and water (0.8 mL). The reaction was stirred at room temperature for 4 hours, then quenched by addition of a potassium carbonate solution (80 g, 30% w/w). The product was extracted using isopropyl alcohol. The organic phase was concentrated under vacuum to dryness. The product was dissolved in isopropyl alcohol (100 mL) and phosphoric acid (1 mL, 85% w/w) was added to crystallize the product as the phosphate salt. The precipitate was filtered and dried in a vacuum oven (5 torr, room temp, slight nitrogen purge) to yield the desired compound as an off-white solid (1.82 g, 4.2 mmol, 43% yield). The product was analyzed by HPLC, HRMS, and NMR.
       1H-NMR (400 MHz, DMSO-d 6): δ 12.05 (s, 1H), 8.64 (s, 1H), 8.56 (d, J=0.9 Hz, 1H), 8.26 (s, 1H), 7.55 (dd, J=3.6, 2.3 Hz, 1H), 7.33 (s, 1H), 6.96 (dd, J=3.6, 1.6 Hz, 1H), 6.76 (s, 1H), 4.57 (td, J=9.7, 4.0 Hz, 1H), 2.88 (dd, J=15.3, 10.0 Hz, 1H), 2.64 (dd, J=15.3, 4.0 Hz, 1H), 2.32 (d, J=9.3 Hz, 1H).
      HPLC method summary: column=Waters XBridge C18, 4.6×150 mm, 3.5 μm column; gradient elution: mobile phase A=10 mM ammonium formate, pH 3.9; mobile phase B=acetonitrile; detection=ultraviolet absorbance at 254 nm. Result: Compound (I)=98.7 area %; retention time=11.1 min.
      HRMS: Agilent 6530 Q-TOF LC/MS system with electrospray ionization in positive mode. The measured time-of-flight mass-to-charge ratio (m/z) is 333.22839 (theoretical value=333.22735).
Clinical data
Trade namesLeqselvi
Other namesCTP-543
License dataUS DailyMedDeuruxolitinib
Routes of
administration
By mouth
Drug classJanus kinase inhibitor
ATC codeNone
Legal status
Legal statusUS: ℞-only[1]
Identifiers
showIUPAC name
CAS Number1513883-39-0as phosphate: 2147706-60-1
PubChem CID72704611as phosphate: 154572727
DrugBankDB18847
ChemSpider115010950
UNII0CA0VSF91Yas phosphate: 8VJ43S4LCM
KEGGD11866as phosphate: D11867
ChEMBLChEMBL4594381
Chemical and physical data
FormulaC17H18N6
Molar mass306.373 g·mol−1
3D model (JSmol)Interactive image
showSMILES

References

King B, Mesinkovska N, Mirmirani P, Bruce S, Kempers S, Guttman-Yassky E, Roberts JL, McMichael A, Colavincenzo M, Hamilton C, Braman V, Cassella JV: Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata. J Am Acad Dermatol. 2022 Aug;87(2):306-313. doi: 10.1016/j.jaad.2022.03.045. Epub 2022 Mar 29. [Article]Yan T, Wang T, Tang M, Liu N: Comparative efficacy and safety of JAK inhibitors in the treatment of moderate-to-severe alopecia areata: a systematic review and network meta-analysis. Front Pharmacol. 2024 Apr 10;15:1372810. doi: 10.3389/fphar.2024.1372810. eCollection 2024. [Article]Barati Sedeh F, Michaelsdottir TE, Henning MAS, Jemec GBE, Ibler KS: Comparative Efficacy and Safety of Janus Kinase Inhibitors Used in Alopecia Areata: A Systematic Review and Meta-analysis. Acta Derm Venereol. 2023 Jan 25;103:adv00855. doi: 10.2340/actadv.v103.4536. [Article]Sardana K, Bathula S, Khurana A: Which is the Ideal JAK Inhibitor for Alopecia Areata – Baricitinib, Tofacitinib, Ritlecitinib or Ifidancitinib – Revisiting the Immunomechanisms of the JAK Pathway. Indian Dermatol Online J. 2023 Jun 28;14(4):465-474. doi: 10.4103/idoj.idoj_452_22. eCollection 2023 Jul-Aug. [Article]FDA Approved Drug Products: LEQSELVI (deuruxolitinib) tablets, for oral use [Link]AJMC: FDA Approves Deuruxolitinib for Alopecia Areata [Link]

Jump up to:a b c d “Archived copy” (PDF). Archived (PDF) from the original on 29 July 2024. Retrieved 26 July 2024.

  1. ^ King, Brett; Mesinkovska, Natasha; Mirmirani, Paradi; Bruce, Suzanne; Kempers, Steve; Guttman-Yassky, Emma; et al. (August 2022). “Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata”Journal of the American Academy of Dermatology87 (2): 306–313. doi:10.1016/j.jaad.2022.03.045ISSN 1097-6787PMID 35364216S2CID 247866262.
  2. ^ SEDEH, Farnam Barati; MICHAELSDÓTTIR, Thorunn Elísabet; HENNING, Mattias Arvid Simon; JEMEC, Gregor Borut Ernst; IBLER, Kristina Sophie (25 January 2023). “Comparative Efficacy and Safety of Janus Kinase Inhibitors Used in Alopecia Areata: A Systematic Review and Meta-analysis”Acta Dermato-Venereologica103: 4536. doi:10.2340/actadv.v103.4536ISSN 0001-5555PMC 10391778PMID 36695751.
  3. ^ “U.S. FDA Approves Leqselvi (deuruxolitinib), an Oral JAK Inhibitor for the Treatment of Severe Alopecia Areata” (Press release). Sun Pharmaceutical. 25 July 2024. Archived from the original on 26 July 2024. Retrieved 26 July 2024 – via PR Newswire.
  4. ^ http://www.leqselvi.com/&a=Prescribing Information
  5. ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information35 (3). hdl:10665/346562.
  6. ^ “Deuruxolitinib”American Medical Association. Retrieved 27 July 2024.

Further reading

Passeron T, King B, Seneschal J, Steinhoff M, Jabbari A, Ohyama M, et al. (2023). “Inhibition of T-cell activity in alopecia areata: recent developments and new directions”Frontiers in Immunology14: 1243556. doi:10.3389/fimmu.2023.1243556PMC 10657858PMID 38022501.

////Deuruxolitinib, alopecia areata, Leqselvi , approvals 2024, fda 2024, C-21543, CTP 543, CTP-543, CTP543, UNII-0CA0VSF91Y, WHO 11622


ZASTAPRAZAN

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ZASTAPRAZAN

2133852-18-1

362.5 g/mol, C22H26N4O

  • 1-Azetidinyl[8-[[(2,6-dimethylphenyl)methyl]amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl]methanone (ACI)
  • azetidin-1-yl-[8-[(2,6-dimethylphenyl)methylamino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl]methanone

JAQBO; JP-1366; OCN-101; Zastaprazan citrate – Onconic Therapeutics, UNII-W9S9KZX5MD

  • Originator Onconic Therapeutics
  • Class Anti-inflammatories; Antiulcers; Azetidines; Imidazoles; Methylamines; Pyridines; Small molecules
  • Mechanism of Action Potassium-competitive acid blockers

Highest Development Phases

  • Registered Erosive oesophagitis
  • Phase III Gastric ulcer; Peptic ulcer
  • 19 Jul 2024Onconic Therapeutics completes a phase III trial in Gastric ulcer in South Korea (PO) (NCT05448001)
  • 03 Jun 2024Onconic Therapeutics plans a phase III trial for Peptic ulcer (Prevention) in South Korea (PO, Capsule) (NCT06439563)
  • 29 May 2024Interim efficacy data from a phase III ZERO-1 trial in erosive esophagitis released by Onconic Therapeutics

Zastaprazan (JP-1366) is a proton pump inhibitor (WO2018008929). Zastaprazan can be used for the research of gastrointestinal inflammatory diseases or gastric acid-related diseases.

SCHEME

Patent

WO2018008929

PATENT

KR1777971 

//////////ZASTAPRAZAN, JAQBO, JP-1366, OCN-101, Zastaprazan citrate, Onconic Therapeutics, Erosive oesophagitis, Phase 3, Gastric ulcer, Peptic ulcer

ATICAPRANT

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ATICAPRANT

JNJ-67953964, WHO 10582

1174130-61-0

BENZAMIDE, 4-(4-(((2S)-2-(3,5-DIMETHYLPHENYL)-1-PYRROLIDINYL)METHYL)PHENOXY)-3-FLUORO-

C26H27FN2O2,  418.512

  • 4-[4-[[(2S)-2-(3,5-Dimethylphenyl)-1-pyrrolidinyl]methyl]phenoxy]-3-fluorobenzamide (ACI)
  • (S)-4-(4-((2-(3,5-Dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)-3-fluorobenzamide
  • 4-(4-{[(2S)-2-(3,5-dimethylphenyl)pyrrolidin-1-yl]methyl}phenoxy)-3-fluorobenzamide
  • Aticaprant
  • CERC 501
  • JNJ 67953964
  • JNJ 67953964AAA
  • LY 2456302
  • S-Aticaprant
  • CERC-501
  • JSPA 0658 JSPA-0658 JSPA0658
  • LY 2456302 LY-2456302 , LY2456302
  • OriginatorEli Lilly and Company
  • DeveloperAvalo Therapeutics; Eli Lilly and Company; Johnson & Johnson Innovative Medicine
  • ClassAntidepressants; Benzamides; Benzene derivatives; Drug withdrawal therapies; Fluorinated hydrocarbons; Pyrrolidines; Smoking cessation therapies
  • Mechanism of ActionOpioid kappa receptor antagonists
  • Phase III Major depressive disorder
  • DiscontinuedAlcoholism; Cocaine-related disorders; Smoking withdrawal
  • 26 Jun 2024Janssen Research & Development initiates a phase III VENTURA-7 trial for Major depressive disorder (Adjunctive treatment) in USA (PO, Tablet) (NCT06514742) (EudraCT2024-511557-21-00)
  • 01 Oct 2023Janssen Pharmaceuticals is now called Johnson & Johnson Innovative Medicine (Janssen Pharmaceuticals website, October 2023)
  • 19 May 2023Chemical structure information added

Aticaprant, also known by its developmental codes JNJ-67953964CERC-501, and LY-2456302, is a κ-opioid receptor (KOR) antagonist which is under development for the treatment of major depressive disorder.[2][3][4] A regulatory application for approval of the medication is expected to be submitted by 2025.[2] Aticaprant is taken by mouth.[1]

Side effects of aticaprant include itching, among others.[4][5] Aticaprant acts as a selective antagonist of the KOR, the biological target of the endogenous opioid peptide dynorphin.[3] The medication has decent selectivity for the KOR over the μ-opioid receptor (MOR) and other targets, a relatively long half-life of 30 to 40 hours, and readily crosses the blood–brain barrier to produce central effects.[4][6]

Aticaprant was originally developed by Eli Lilly, was under development by Cerecor for a time, and is now under development by Janssen Pharmaceuticals.[2] As of July 2022, it is in phase 3 clinical trials for major depressive disorder.[2] Like other kappa opioid antagonists currently under clinical investigation for the treatment of major depression, its efficacy may be compromised by the countervailing activation of pro-inflammatory cytokines in microglia within the CNS.[7]

Aticaprant was also under development for the treatment of alcoholismcocaine use disorder, and smoking withdrawal, but development for these indications was discontinued.[2]

Pharmacology

Pharmacodynamics

Aticaprant is a potentselective, short-acting (i.e., non-“inactivating”) antagonist of the KOR (Ki = 0.81 nM vs. 24.0 nM and 155 nM for the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), respectively; approximately 30-fold selectivity for the KOR).[8][9][10] The drug has been found to dose-dependently block fentanyl-induced miosis at 25 mg and 60 mg in humans (with minimal to no blockade at doses of 4 to 10 mg), suggesting that the drug significantly occupies and antagonizes the MOR at a dose of at least 25 mg but not of 10 mg or less.[10] However, a more recent study assessing neuroendocrine effects of the drug in normal volunteers and subjects with a history of cocaine dependence reported observations consistent with modest MOR antagonism at the 10 mg dose.[11] In animal models of depression, aticaprant has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.[12]

Positron emission tomography imaging revealed that brain KORs were almost completely saturated by the drug 2.5 hours following a single dose of 10 mg, which supported the 4 mg to 25 mg dosages that aticaprant is being explored at in clinical trials.[13][14] Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[15][14] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[15][14] No serious side effects were observed, and all side effects seen were mild to moderate and were not thought to be due to aticaprant.[14]

Pharmacokinetics

The oral bioavailability of aticaprant is 25%.[1] The drug is rapidly absorbed, with maximal concentrations occurring 1 to 2 hours after administration.[1] It has an elimination half-life of 30 to 40 hours in healthy subjects.[1] The circulating levels of aticaprant increase proportionally with increasing doses.[1] Steady-state concentrations are reached after 6 to 8 days of once-daily dosing.[1] Aticaprant has been shown to reproducibly penetrate the blood–brain barrier.[13][14]

History

Aticaprant was originally developed by Eli Lilly under the code name LY-2456302.[2] It first appeared in the scientific literature in 2010 or 2011.[16][17] The compound was first patented in 2009.[18]

In February 2015, Cerecor Inc. announced that they had acquired the rights from Eli Lilly to develop and commercialize LY-2456302 (under the new developmental code CERC-501).[19]

As of 2016, aticaprant has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[20][12] A phase II study of aticaprant in heavy smokers was commenced in early 2016 and results of the study were expected before the end of 2016.[14] Aticaprant failed to meet its main endpoint for nicotine withdrawal in the study.[21]

In August 2017, it was announced that Cerecor had sold its rights to aticaprant to Janssen Pharmaceuticals.[22][21] Janssen was also experimenting with esketamine for the treatment of depression as of 2017.[21]

Research

In addition to major depressive disorder, aticaprant was under development for the treatment of alcoholismcocaine use disorder, and smoking withdrawal.[2] However, development for these indications was discontinued.[2]

See also

κ-Opioid receptor § Antagonists

SCHEME

SYNTHESIS

WO/2024/178082COMPOSITION OF OPIOID RECEPTOR MODULATOR AND MDMA FOR USE THEREOF

WO/2024/173843QUINOLINE DERIVATIVES WHICH ACT AS KAPPA-OPIOID RECEPTOR ANTAGONISTS

20240238245COMPOSITIONS AND METHODS FOR THE TREATMENT OF DEPRESSION

20240189274Compositions And Methods For The Treatment Of Depression

WO/2024/102802ZELATRIAZIN FOR THE TREATMENT OF DEPRESSION

WO/2024/100285TREATMENT OF A COGNITIVE DISORDER WITH AN AGENT THAT INCREASES THE..

117615757Compositions and methods for treating depression

117142999Racemization method of drug intermediate

20230348377PURE FORMS OF CRYSTALLINE ATICAPRANT

WO/2023/170550POLYMORPH FORMS OF ATICAPRANT FOR USE IN TREATING MAJOR DEPRESSIVE DISORDER

WO/2023/170547PURE FORMS OF CRYSTALLINE ATICAPRANT

20230277499Forms of aticaprant

20230277500COMPOSITIONS COMPRISING ATICAPRANT

WO/2023/164385NEUROACTIVE STEROIDS FOR TREATMENT OF GASTROINTESTINAL DISEASES OR CONDITIONS

20090186873Kappa selective opioid receptor antagonist

WO/2009/094260KAPPA SELECTIVE OPIOID RECEPTOR ANTAGONIST

20100197669Kappa selective opioid receptor antagonist

2252581KAPPA SELECTIVE OPIOID RECEPTOR ANTAGONIST

201500053151-substituted 4-arylpiperazine as kappa opioid receptor antagonists

WO/2013/0864961-SUBSTITUTED 4-ARYLPIPERAZINE AS KAPPA OPIOID RECEPTOR ANTAGONISTS

101925576Kappa selective opioid receptor antagonist

PAPERS

ACS Omega (2020), 5(41), 26938-26945 https://pubs.acs.org/doi/full/10.1021/acsomega.0c04329

REF https://pubs.acs.org/doi/suppl/10.1021/acsomega.0c04329/suppl_file/ao0c04329_si_001.pdf

N-Methoxy-N-methyl-4-chlorobutyramide (S1). To a mixture of N,O-dimethylhydroxylamine hydrochloride (95.0 mmol, 9.27 g) in CH2Cl2 (150 mL) was
added 2 M NaOH (300 mmol, 150 mL) and 4-chlorobutyryl chloride (100 mmol,
11.2 mL) at 0 ˚C. The mixture was stirred for 42 h at room temperature. The
organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phase was washed with 2 M NaOH (100 mL), dried over Na2SO4, filtered, and concentrated
to afford the title comlund in 75% yield as a colorless liquid.
1H NMR (400 MHz, CDCl3) : 2.08-2.15
(m, 2H), 2.63 (t, J = 7.0 Hz, 2H), 3.19 (s, 3H), 3.64 (t, J = 6.3 Hz, 2H), 3.71 (s, 3H).
13C{
1H} NMR (100
MHz, CDCl3) : 27.1, 28.6, 32.1, 44.6, 61.1. IR (max/cm-1
): 2965, 2940, 2821, 1656, 14421, 1417, 1387,
1178, 1107, 997. HRMS (ESI+): calculated for [M+Na]+
: 188.0449, found: 188.0450.

4-Chloro-1-(3,5-dimethylphenyl)butan-1-one (S2). To a mixture of N-methoxy-N-methyl-4-chlorobutyramide (S1, 65.0 mmol, 10.8 g) in anhydrous Et2O
(100 mL) was added dropwise 3,5-dimethylphenylmagnesium bromide (ca. 1 M
in Et2O, ca. 130 mmol, prepared from 1-bromo-3,5-dimethylbenzene (130 mmol,
17.7 mL) and Mg turnings (169 mmol, 4.11 g) in anhydrous Et2O (130 mL)) over 1 h at -40 ˚C under Ar.
The reaction mixture was stirred at room temperature for 20 h. After cooling to 0 ˚C, saturated NH4Cl
solution (200 mL) was added. The organic phase was separated, washed with water (100 mL) and brine
(100 mL), dried over Na2SO4, and filtered. After concentration, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent) to afford the title compound in 91% yield as a greenish
yellow liquid.
1H NMR (400 MHz, CDCl3) : 2.18-2.25 (m, 2H), 2.38 (s, 6H), 3.15 (t, J = 7.0 Hz, 2H),
3.67 (t, J = 6.3 Hz, 2H), 7.21 (s, 1H), 7.58 (s, 2H). 13C{
1H} NMR (100 MHz, CDCl3) : 21.2, 26.8, 35.4,
44.7, 125.8, 134.8, 136.8, 138.3, 199.4. IR (max/cm-1
): 3047, 3006, 2961, 2920, 2868, 1443, 1411, 1322,
1303, 1181, 1159, 844, 785, 687. HRMS (APCI+): calculated for [M+H]+
: 211.0884, found: 211.0884.

(RS)-N-(4-Chloro-1-(3,5-dimethylphenyl)butylidene)-tertbutanesulfinamide (S3). Ti(OEt)4 (100 mol, 21.0 mL) was added to a mixture
of (RS)-tert-butanesulfinamide (1.0 M in THF, 50 mmol, 50 mL) and 4-chloro1-(3,5-dimethylphenyl)butan-1-one (S2, 50.0 mmol, 10.5 g) under N2. The mixture was refluxed for 48 h. After cooling to room temperature, brine (100 mL)
was added, and the resulting mixture was filtered over Celite using EtOAc (ca.
300 mL). The organic was separated, dried over Na2SO4, and filtered. After concentration under reduced
pressure, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent) to
afford the title compound in 57% yield as a brown viscous liquid.
1H NMR (400 MHz, CDCl3) : 1.33
(s, 9H), 2.10-2.22 (m, 2H), 2.36 (s, 6H), 3.27 (s, 1H), 3.43 (s, 1H), 3.64 (t, J = 6.5 Hz, 2H), 7.13 (s, 1H),
7.47 (s, 2H).
13C{
1H} NMR (100 MHz, CDCl3) : 21.3, 22.7, 30.2, 31.6, 44.7, 57.7, 125.2, 133.4, 137.6,
138.2, 178.6. IR (max/cm-1
): 3046, 2958, 2922, 2866, 1599, 1577, 1455, 1361, 1320, 1308, 1069, 856.
HRMS (ESI+): calculated for [M+H]
+
: 314.1340, found: 314.1344. []D
20 +11.0 (c = 1.01, CH2Cl2).

(RS,S)-1-tert-Butylsulfinyl-2-(3,5-dimethylphenyl)pyrrolidine (S4). To a solution of (RS)-N-(4-chloro-1-(3,5-dimethylphenyl)butylidene)-tert-butanesulfinamide
(S3, 25.6 mmol, 8.06 g) in anhydrous THF (100 mL) at -78 °C was added LiBEt3H
(28 mmol, 0.5 M in THF, 28.2 mL) under Ar. The reaction was stirred at -78 °C for
1 h, subsequently allowed to warm up to room temperature and stirred for additional
20 h. Saturated NaHCO3 solution (80 mL) was slowly added. The mixture was filtered and extracted
with EtOAc (3 × 100 mL). The combined organic phase was dried over Na2SO4 and filtered. After
concentration, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent)
to afford the title compound in 72% yield as pale yellow solid. mp.: 56 ˚C. 1H NMR (400 MHz, CDCl3)
: 1.12 (s, 9H), 1.74-1.90 (m, 3H), 1.93-2.02 (m, 1H), 2.18-2.27 (m, 1H), 2.30 (s, 6H), 2.94-3.02 (m, 1H),
3.85-3.91 (m, 1H), 4.55-4.59 (m, 1H), 6.88 (s, 1H), 6.90 (s, 2H).
13C{
1H} NMR (100 MHz, CDCl3) :
21.3, 23.8, 26.3, 36.0, 42.1, 57.2, 69.2, 125.0, 128.7, 137.7, 143.2. IR (max/cm-1
): 3023, 2957, 2920,
2866, 1607, 1471, 1360, 1061, 957, 847. HRMS (ESI+): calculated for [M+Na]+
: 302.1549, found:
302.1548. []D
20
-137 (c = 0.49, CH2Cl2)

(S)-2-(3,5-Dimethylphenyl)pyrrolidine hydrochloride (1j•HCl). To a solution
of (RS,S)-1-tert-butylsulfinyl-2-(3,5-dimethylphenyl)pyrrolidine (S4, 14.7 mmol,
4.12 g) in dioxane (250 mL) was added dropwise HCl (ca. 150 mmol, 4 M in dioxane, 38 mL). The mixture was stirred for 1 h at room temperature under N2, and
then the mixture was concentrated under reduced pressure. Then, Et2O (200 mL) was added to the residue
and the mixture was cooled to 0 ˚C. The precipitate was collected by filtration, washed with Et2O (40
mL), and dried under reduced pressure to afford the title compound in 94% yield as white solid. mp.: 198
˚C. 1H NMR (400 MHz, D2O) : 2.00-2.15 (m, 3H), 2.18 (s, 6H), 2.27-2.35 (m, 1H), 3.27-3.36 (m, 2H),
4.45 (t, J = 8.0 Hz, 1H), 6.97 (s, 2H), 7.01 (s, 1H). 13C{
1H} NMR (100 MHz, D2O) : 20.9, 24.19, 30.9,
46.0, 63.8, 119.79, 125.6, 131.4, 135.3, 140.1. IR (max/cm-1
): 3033, 3012, 2970, 2855, 2743, 2571, 2480,
1608, 1590, 1414, 850. HRMS (ESI+): calculated for [M-Cl]
+
: 176.1434, found: 176.1435. []D
20 +7.1
(c = 1.01, MeOH).

(S)-2-(3,5-Dimethylphenyl)pyrrolidine (1j). To a suspension of (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride (1j•HCl, 13.5 mmol, 2.86 g) in anhydrous Et2O
(200 mL) was added a saturated solution of NaHCO3 (200 mL). The resulting mixture
was stirred for 20 min at room temperature. The organic was separated and the aqueous
phase was extracted with Et2O (2 × 100 mL). The combined organic phase was dried over MgSO4 and
filtered. The solvent was removed under reduced pressure to afford the title compound as a pale yellow
liquid in 99% yield.
1H NMR (400 MHz, CDCl3) : 1.60-1.71 (m, 1H), 1.78-1.96 (m, 2H), 1.98 (s, 1H),
2.11-2.19 (m, 1H), 2.30 (s, 6H), 2.95-3.02 (m, 1H), 3.17-3.23 (m, 1H), 4.03 (t, J = 7.7 Hz, 1H), 6.87 (s,
1H), 6.97 (s, 2H). 13C{
1H} NMR (100 MHz, CDCl3) : 21.3, 25.5, 34.2, 46.9, 62.6, 124.2, 128.4, 137.8,
144.7. IR (max/cm-1
): 3332, 3010, 2960, 2915, 2869, 1605, 1458, 1101, 845. HRMS (ESI+): calculated
for [M+H]+
: 176.1434, found: 176.1436. []D
20
-30.5 (c = 1.01, MeOH). Chiral HPLC (ChiralPak ODH,  4.6 mm × L 250 mm, hexane:2-propanol = 90:10, 0.5 mL/min,  = 254 nm): tR/min = 18.7 (1%),
19.8 (99%).

3-Fluoro-4-(4-formylphenoxy)benzonitrile2
(S5). A mixture of 3,4-
difluorobenzonitrile (35.0 mmol, 4.87 g), 4-hydroxybenzaldehyde (35.0
mmol, 4.27 g), and K2CO3 (70.0 mmol, 9.67 g) in N,N-dimethylacetamide
(90 mL) was stirred at 100 ˚C for 2 h under N2. After cooling, the reaction
mixture was poured into ice water. White precipitate was collected by filtration, washed with water, and dried under reduced pressure to afford the title compound as pale yellow
solid in 82% yield. mp.: 101 ˚C. 1H NMR (400 MHz, CDCl3) : 7.11-7.15 (m, 2H), 7.20 (t, J = 8.2 Hz,
1H), 7.49-7.51 (m, 1H), 7.54 (dd, J = 9.7, 1.9 Hz, 1H), 7.91-7.94 (m, 2H), 9.98 (s, 1H).
13C{
1H} NMR
(100 MHz, CDCl3) : 109.1 (d, 3
JC-F = 8.2 Hz), 117.1 (d, 4
JC-F = 2.5 Hz), 117.9, 121.3 (d, 2
JC-F = 21.3 Hz),
122.5 (d, 4
JC-F = 1.6 Hz), 129.6 (d, 3
JC-F = 4.1 Hz), 132.1, 132.7, 147.0 (d, 2
JC-F = 11.5 Hz), 153.6 (d, 1
JCF = 254.8 Hz), 160.7, 190.4. IR (max/cm-1
): 3100, 3060, 2846, 2812, 2761, 2232, 1697, 1687, 1585, 1497,
1277, 1216, 1166, 1114, 836. HRMS (APCI+): calculated for [M+H]+
: 242.0612, found: 242.0616.

3-Fluoro-4-(4-formylphenoxy)benzamide2
(2f). To a mixture of 3-
fluoro-4-(4-formylphenoxy)benzonitrile (S5, 26.0 mmol, 6.27 g) and
K2CO3 (13.0 mmol, 1.80 g) in DMSO (24 mL) was added dropwise 35%
H2O2 (ca. 29 mmol, 3.1 mL) at 10 ˚C over 5 min. The reaction mixture
was stirred at room temperature for 2 h. The reaction mixture was
poured into ice water. White precipitate was collected by filtration, washed with water, and dried under
reduced pressure to afford the title compound as white solid in 92% yield. mp. 129 ˚C. 1H NMR (400
MHz, (D3C)2SO) : 9.96 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.93 (dd, J = 1.9, 10.0 Hz, 1H),

7.85-7.82 (m, 1H), 7.58 (s, 1H), 7.42 (t, J = 8.2 Hz, 1 H), 7.20 (d, J = 8.2 Hz, 2H).
13C{
1H} NMR (100
MHz, (D3C)2SO) : 116.6 (d, 2
JC-F = 19.7 Hz), 116.9, 122.6, 125.1 (d, 4
JC-F = 3.3 Hz), 131.9 (d, 2
JC-F =
21.3 Hz), 132.1, 132.7 (d, 3
JC-F = 5.7 Hz), 143.7 (d, 3
JC-F = 12.3 Hz), 153.1 (d, 1
JC-F = 248.2 Hz), 161.3,
165.8, 191.5. IR (max/cm-1
): 3356, 3185, 2844, 1668, 1598, 1504, 1433, 1382, 1269, 1218, 1156, 1128,

  1. HRMS (ESI+): calculated for [M+Na]
    +
    : 282.0537, found: 282.0541. HRMS (APCI+): calculated
    for [M+H]+
    : 260.0717, found: 260.0716.

NEXT

Reaction Chemistry & Engineering (2022), 7(8), 1779-1785

Journal of Medicinal Chemistry (2011), 54(23), 8000-8012

Clinical data
Other namesJNJ-67953964; CERC-501; LY-2456302
Routes of
administration
By mouth[1]
Pharmacokinetic data
Bioavailability25%[1]
Elimination half-life30–40 hours[1]
Identifiers
showIUPAC name
CAS Number1174130-61-0
PubChem CID44129648
IUPHAR/BPS9194
DrugBankDB12341
ChemSpider28424203
UNIIDE4G8X55F5
KEGGD11831
ChEMBLChEMBL1921847
CompTox Dashboard (EPA)DTXSID90151777 
Chemical and physical data
FormulaC26H27FN2O2
Molar mass418.512 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

References

Jump up to:a b c d e f g h i Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, et al. (2016). “Major Depressive Disorder and Kappa Opioid Receptor Antagonists”Translational Perioperative and Pain Medicine1 (2): 4–16. PMC 4871611PMID 27213169.

  1. Jump up to:a b c d e f g h “CERC 501”Adis Insight. 30 January 2018.
  2. Jump up to:a b Browne CA, Wulf H, Lucki I (2022). “Kappa Opioid Receptors in the Pathology and Treatment of Major Depressive Disorder”. In Liu-Chen LY, Inan S (eds.). The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 493–524. doi:10.1007/164_2020_432ISBN 978-3-030-89073-5PMID 33580854S2CID 231908782.
  3. Jump up to:a b c Reed B, Butelman ER, Kreek MJ (2022). “Kappa Opioid Receptor Antagonists as Potential Therapeutics for Mood and Substance Use Disorders”. In Liu-Chen LY, Inan S (eds.). The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 473–491. doi:10.1007/164_2020_401ISBN 978-3-030-89073-5PMID 33174064S2CID 226305229.
  4. ^ Krystal AD, Pizzagalli DA, Smoski M, Mathew SJ, Nurnberger J, Lisanby SH, et al. (May 2020). “A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia”Nature Medicine26 (5): 760–768. doi:10.1038/s41591-020-0806-7PMC 9949770PMID 32231295S2CID 256839849.
  5. ^ Dhir A (January 2017). “Investigational drugs for treating major depressive disorder”. Expert Opinion on Investigational Drugs26 (1): 9–24. doi:10.1080/13543784.2017.1267727PMID 27960559S2CID 45232796.
  6. ^ Missig G, Fritsch EL, Mehta N, Damon ME, Jarrell EM, Bartlett AA, et al. (January 2022). “Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses”Pharmacology, Biochemistry, and Behavior212: 173301. doi:10.1016/j.pbb.2021.173301PMC 8748402PMID 34826432.
  7. ^ Rorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, et al. (February 2014). “LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders”. Neuropharmacology77: 131–144. doi:10.1016/j.neuropharm.2013.09.021PMID 24071566S2CID 3230414.
  8. ^ Lowe SL, Wong CJ, Witcher J, Gonzales CR, Dickinson GL, Bell RL, et al. (September 2014). “Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects”. Journal of Clinical Pharmacology54 (9): 968–978. doi:10.1002/jcph.286PMID 24619932S2CID 14814449.
  9. Jump up to:a b Rorick-Kehn LM, Witcher JW, Lowe SL, Gonzales CR, Weller MA, Bell RL, et al. (October 2014). “Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human”The International Journal of Neuropsychopharmacology18 (2): pyu036. doi:10.1093/ijnp/pyu036PMC 4368892PMID 25637376.
  10. ^ Reed B, Butelman ER, Fry RS, Kimani R, Kreek MJ (March 2018). “Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence”Neuropsychopharmacology43 (4): 928. doi:10.1038/npp.2017.245PMC 5809790PMID 29422497.
  11. Jump up to:a b Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). “Antagonists of the kappa opioid receptor”. Bioorganic & Medicinal Chemistry Letters24 (9): 2021–2032. doi:10.1016/j.bmcl.2014.03.040PMID 24690494.
  12. Jump up to:a b “Publication Reports Human Brain Penetration and Target Engagement of Cerecor’s Oral Kappa Opioid Receptor Antagonist, CERC-501”BusinessWire. 11 December 2015.
  13. Jump up to:a b c d e f Naganawa M, Dickinson GL, Zheng MQ, Henry S, Vandenhende F, Witcher J, et al. (February 2016). “Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050”The Journal of Pharmacology and Experimental Therapeutics356 (2): 260–266. doi:10.1124/jpet.115.229278PMC 4727157PMID 26628406.
  14. Jump up to:a b Placzek MS (August 2021). “Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography”. In Liu-Chen LY, Inan S (eds.). The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 547–577. doi:10.1007/164_2021_498ISBN 978-3-030-89073-5PMID 34363128S2CID 236947969.
  15. ^ Zheng MQ, Nabulsi N, Kim SJ, Tomasi G, Lin SF, Mitch C, et al. (March 2013). “Synthesis and evaluation of 11C-LY2795050 as a κ-opioid receptor antagonist radiotracer for PET imaging”Journal of Nuclear Medicine54 (3): 455–463. doi:10.2967/jnumed.112.109512PMC 3775344PMID 23353688.
  16. ^ Mitch CH, Quimby SJ, Diaz N, Pedregal C, de la Torre MG, Jimenez A, et al. (December 2011). “Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer”. Journal of Medicinal Chemistry54 (23): 8000–8012. doi:10.1021/jm200789rPMID 21958337.
  17. ^ “WO2009094260A1 – Kappa selective opioid receptor antagonist”Google Patents. 13 January 2009. Retrieved 29 August 2022.
  18. ^ “Cerecor Bolsters Clinical Pipeline with Acquisition of Phase 2-ready Kappa Opioid Receptor Antagonist from Eli Lilly and Company”cerecor.com. February 20, 2015. Archived from the original on 2015-02-23. Retrieved March 18, 2015.
  19. ^ Rankovic Z, Hargreaves R, Bingham M (2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 314–317. ISBN 978-1-84973-365-6.
  20. Jump up to:a b c Bushey R (August 2017). “J&J Adds New Depression Drug to Portfolio”Drug Discovery and Development Magazine.
  21. ^ “Cerecor Announces Divestiture of CERC-501 to Janssen Pharmaceuticals, Inc”Marketwired. August 2017. Archived from the original on 2017-09-01. Retrieved 2017-09-01.

Further reading

Aticaprant – Eli Lilly and Company/Janssen Pharmaceuticals – AdisInsight

//////ATICAPRANT, CERC-501, JSPA 0658, JSPA-0658, JSPA0658, LY 2456302, LY-2456302, LY2456302, Phase 3, ELI LILLY, Major depressive disorder, JNJ-67953964, WHO 10582

Zamaporvint

$
0
0

Zamaporvint

RXC004, PHASE 2

1H-IMIDAZOLE-1-ACETAMIDE, 5-METHYL-N-(5-(2-PYRAZINYL)-2-PYRIDINYL)-4-(2-(TRIFLUOROMETHYL)-4-PYRIDINYL)-

5-METHYL-N-(5-(2-PYRAZINYL)-2-PYRIDINYL)-4-(2-(TRIFLUOROMETHYL)-4-PYRIDINYL)-1H-IMIDAZOLE-1-ACETAMIDE

UNII


M56M7CHN8E
Molecular Weight439.39
FormulaC21H16F3N7O
CAS No.1900754-56-4

Zamaporvint (RXC004) is an orally active and selective inhibitor of Wnt. Zamaporvint targete membrane-bound o-acyltransferase Porcupine and inhibited Wnt ligand palmitoylation, secretion, and pathway activation. Zamaporvint displays a favorable pharmacokinetic profile and shows potent antiproliferative effects in Wnt ligand-dependent colorectal and pancreatic cell lines. Zamaporvint possesses multiple antitumor mechanisms and can be used in cancer research.

SCHEME

PATENT

Redx Pharma PLC

WO2016055786

Example 9: 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]-N-(5-pyrazin-2- yl-2-pyridyl)acetamide

To a stirred solution of lithium 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetate (1.04g, 3.57mmol) and 5-pyrazin-2-ylpyridin-2-amine (738mg, 4.29mmol) in THF (35mL) was added Ν,Ν-diisopropylethylamine (1.56mL, 8.93mmol) and propylphosphonic anhydride (6.38mL, 10.7mmol) and the resulting solution heated to 70°C. Reaction was monitored by LCMS and after 2 hrs further propylphosphonic anhydride (2.13mL, 3.57mmol) and N,N-diisopropylethylamine (0.6mL) were added the solution was allowed to cool to room temperature and stirred over the weekend. The solution was diluted with water and EtOAc and partitioned. The aqueous was washed with EtOAc (x2) before the combined organics were washed with brine. Product precipitated and was isolated by filtration and loaded onto a MeOH primed 10g SCX cartridge, washing with MeOH and eluting with 1 M NH3 MeOH solution. The ammonia methanol solution was concentrated to dryness in vacuo to afford an off white solid which was then dried in a vacuum oven for 2hrs. The organics were separated from the filtrate, dried (sodium sulphate), filtered and concentrated to dryness in vacuo to afford a light brown foam containing product of ~95% purity. This was dissolved in DCM and purified by flash column chromatography (25g SiO2, 70-100% EtOAc in heptane, then 0-5% MeOH/EtOAc). Appropriate fractions were combined and concentrated to dryness in vacuo to afford an off white solid. The solids were combined to give 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (1.22g, 2.77mmol, 78% yield) as an off white solid.

MS Method 2: RT: 1.45 min, ES+ m/z 440.1 [M+H]+

1H NMR (400MHz, DMSO) δ/ppm: 11.27 (bs, 1 H), 9.32-9.33 (d, J=1.6Hz, 1 H), 8.70-8.75 (m, 2H), 8.64-8.65 (d, J=2.4Hz, 1 H), 8.54-8.58 (dd, J=2.4, 8.8Hz, 1 H), 8.17-8.19 (d, J=9.2Hz, 1 H), 8.09 (s, 1 H), 7.92-7.94 (d, J=4.4Hz, 1 H), 7.85 (s, 1 H), 5.12 (s, 2H), 2.45 (s, 3H).

/////////Zamaporvint, RXC004, RX C004, PHASE 2

Atilotrelvir

$
0
0

Atilotrelvir, BDBM622370, GST-HG171

2850365-55-6, ALIGOS THERAPEUTICS, INC

511.5 C24H32F3N5O4

(1S,3S,4R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]spiro[2-azabicyclo[2.2.1]heptane-5,1′-cyclopropane]-3-carboxamide

Spiro[2-azabicyclo[2.2.1]heptane-5,1′-cyclopropane]-3-carboxamide, N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-pyrrolidinyl]ethyl]-2-[(2S)-3,3-dimethyl-1-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyl]-, (1S,3S,4R)-

Atilotrelvir (GST-HG171) is antiviral agent, can inhibit coronavirus, picornavirus and norovirus infection.

SCHEME

SYNTHESIS

Patents are available for this chemical structure:

https://patentscope.wipo.int/search/en/result.jsf?inchikey=GTRJFXDJASEGSW-KBCNZALWSA-N

PATENT

US20230312571, Embodiment 11

PATENT

WO2023043816 EX 50

[0312] To a stirred mixture of (1R,4S,6S)-5-(tert-butoxycarbonyl)-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropane]-6-carboxylic acid (120 mg, 0.449 mmol, 1.0 eq.) and o-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (204 mg, 0.539 mmol, 1.2 eq.) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (348 mg, 2.69 mmol, 6.0 eq.). The mixture was stirred for 10 min at 0 °C, and then (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (102 mg, 0.494 mmol, 1.1 eq.) was added. The mixture was stirred for 1 h at rt. The crude product was purified by C18 column with CH3CN:Water (0.05% FA). The desired fractions were concentrated under reduced pressure to provide tert-butyl (1R,4S,6S)-6-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropane]-5-carboxylate (120 mg, 60 %) as a white solid. LC-MS (ESI, m/z): 421 [M+H]+.

[0313] To a stirred mixture of tert-butyl (1R,4S,6S)-6-{[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl}-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropane]-5-carboxylate (140 mg, 0.333 mmol, 1.0 eq.) in DCM (1 mL) was added hydrogen chloride (3 mL, 2M in Et2O). The mixture was stirred for 1 h at rt, and then concentrated under reduced pressure to afford (2S)-2-[(1R,4S,6S)-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropan]-6-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (110 mg, crude) as a white solid. LC-MS (ESI, m/z): 321 [M+H]+.

[0314] To a stirred mixture of (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid (70.7 mg, 0.311 mmol, 1.1 eq.) and o-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (129 mg, 0.340 mmol, 1.2 eq.) in DMF (2 mL) were added N-ethyl-N-isopropylpropan-2-amine (219 mg, 1.69 mmol, 6.0 eq.). The mixture was stirred for 10 min at 0 °C, and then (2S)-2-[(1R,4S,6S)-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropan]-6-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide hydrochloride (101 mg, 0.283 mmol, 1.0 eq.) was added. The mixture was stirred for 1 h at rt and purified by C18 column with CH3CN/Water (0.05% FA). The desired fractions were concentrated under reduced pressure to provide (2S)-2-[(1R,4S,6S)-5-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropan]-6-ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (90.0 mg, 57 %) as a white solid. LC-MS (ESI, m/z): 530 [M+H]+.

[0315] To a stirred mixture of (2S)-2-[(1R,4S,6S)-5-[(2S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl]-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropan]-6- ylformamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (90.0 mg, 0.170 mmol, 1.0 eq.) and pyridine (53.7 mg, 0.680 mmol, 4.0 eq.) in DCM (2 mL) was added trifluoroacetic anhydride (64.2 mg, 0.306 mmol, 1.8 eq.). The mixture was stirred for 1 h at rt. The reaction was quenched with water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by prep-HPLC with the following conditions (Column:  Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 38% B to 68% B in 7 min, 68% B; Wave Length: 254 nm; RT1(min): 5.07) to afford (1R,4S,6S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-5-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-5- azaspiro[bicyclo[2.2.1]heptane-2,1′-cyclopropane]-6-carboxamide (18.2 mg, 20%) as a white solid. 1H NMR (400 MHz, 
8.45-9.03 (m, 1H), 7.30- 7.65 (m, 1H), 4.80-4.98 (m, 1H), 4.42-4.76 (m, 2H), 4.02-4.18 (m, 1H), 3.10-3.30 (m, 2H), 2.30-2.44 (m, 1H), 1.97-2.25 (m, 3H), 1.59-1.97 (m, 5H), 1.40-1.58 (m, 1H), 0.90-1.06 (m, 9H), 0.61-0.83 (m, 2H), 0.21-0.54 (m, 2H). LC-MS (ESI, m/z): 512 [M+H]+.

REF

[1]. Chen, et al. Ring-modified proline short peptide compound and application for treating covid-19. World Intellectual Property Organization, WO2022218442 A1. 2022-10-20.

//////////Atilotrelvir, BDBM622370, 2850365-55-6, ALIGOS THERAPEUTICS, GST-HG171, GST HG171, GSTHG-171, GSTHG 171,

Votoplam

$
0
0

Votoplam

CAS 2407849-89-0

Molecular FormulaC21H25N9O
Molecular Weight419.4829
PHENOL, 2-(3-(2,2,6,6-TETRAMETHYL-4-PIPERIDINYL)-3H-1,2,3-TRIAZOLO(4,5-C)PYRIDAZIN-6-YL)-5-(2H-1,2,3-TRIAZOL-2-YL)-
2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)triazolo[4,5-c]pyridazin-6-yl]-5-(triazol-2-yl)phenol

UNII D7EZ7B585X

Votoplam is a gene splicing modulator, used to inhibit Huntington’s disease.

Target: DNA/RNA Synthesis
Pathway: Cell Cycle/DNA Damage

Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is between three and seven individuals per 100,000 in populations of western European descent. In North America, an estimated 30,000 people have HD, while an additional 200,000 people are at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the “mutant” huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded poly-glutamine (polyQ) stretch, also known as a “CAG repeat” sequence. There are no current small molecule therapies targeting the underlying cause of the disease, leaving a high unmet need for medications that can be used for treating or ameliorating HD. Consequently, there remains a need to identify and provide small molecule compounds for treating or ameliorating HD.

SCHEME

PATENT

PTC Therapeutics Inc., WO2022104058

WO2022103980’

PATENT

WO2020005873

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020005873&_cid=P20-M1EWD1-90833-1

Example 37

Preparation of Compound 163

References

[1] Annalisa Gatto et al. Audiol Res. Otological Planning Software-OTOPLAN: A Narrative Literature Review

[2] Dimitrios Paouris et al. J Pers Med. Validation of Automatic Cochlear Measurements Using OTOPLAN® Software

[3] Andrea Lovato et al. Otol Neurotol. OTOPLAN in Cochlear Implantation for Far-advanced Otosclerosis

[4] Kranti Bhavana et al. Indian J Otolaryngol Head Neck Surg. OTOPLAN-Based Study of Intracochlear Electrode Position Through Cochleostomy and Round Window in Transcanal Veria Technique

[5] Giampietro Ricci et al. J Int Adv Otol. OTOPLAN, Cochlear Implant, and Far-Advanced Otosclerosis: Could the Use of Software Improve the Surgical Final Indication?

REFERENCES
[1]. Sydorenko, et al. Preparation of heterocyclic and heteroaryl compounds for treating Huntington’s disease. World Intellectual Property Organization, WO2020005873 A1.
2020-01-02.

20240216369THE USE OF A SPLICING MODULATOR FOR A TREATMENT SLOWING PROGRESSION OF HUNTINGTON’S DISEASE

20240132509HETEROCYCLIC AND HETEROARYL COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE

20230405000TABLET FOR USE IN TREATING HUNTINGTON’S DISEASE AND METHOD OF MAKING THE SAME

20220162610NOVEL RNA TRANSCRIPT

20210238186Heterocyclic and heteroaryl compounds for treating Huntington’s disease

3814357HETEROCYCLIC AND HETEROARYL COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE

112654625HETEROCYCLIC AND HETEROARYL COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE

WO/2020/005873HETEROCYCLIC AND HETEROARYL COMPOUNDS FOR TREATING HUNTINGTON’S DISEASE

/////////PTC Therapeutics, Votoplam

ATUZAGINSTAT

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ATUZAGINSTAT, COR388

cas 2211981-76-7

Cyclopentanecarboxamide, N-[(1S)-5-amino-1-[2-(2,3,6-trifluorophenoxy)acetyl]pentyl]-

Cyclopentanecarboxamide, n-((1s)-5-amino-1-(2-(2,3,6-trifluorophenoxy)acetyl)pentyl)-N-((3s)-7-amino-2-oxo-1-(2,3,6- trifluorophenoxy)heptan-3-yl)cyclopentanecarboxamide

C19H25F3N2O3

386.415

UNII-DGN7ROZ8EN

  • OriginatorCortexyme
  • DeveloperQuince Therapeutics
  • ClassAnti-inflammatories; Antibacterials; Antidementias; Antineoplastics; Antiparkinsonians; Neuroprotectants; Small molecules
  • Mechanism of ActionPeptide hydrolase inhibitors
  • Phase II/IIIAlzheimer’s disease
  • Phase IIPeriodontal disorders
  • PreclinicalParkinson’s disease; Squamous cell cancer
  • 27 Jan 2023COR 388 licensed to Lighthouse Pharmaceuticals in the US
  • 01 Aug 2022Atuzaginstat is available for licensing as of 01 Aug 2022. http://www.quincetx.com
  • 01 Aug 2022Cortexyme is now called Quince Therapeutics

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This small molecule is an orally available protease inhibitor targeting the lysine proteases of the periodontal pathogen Porphyromonas gingivalis. Known as gingipains, these proteases penetrate gingival tissue and cause inflammation at the site of periodontitis (O’Brien-Simpson et al., 2009). Periodontitis has been linked epidemiologically to cognitive impairment, and P. gingivalis bacterial lipopolysaccharide has been detected in postmortem brain tissue of people with AD (Poole et al., 2013). Oral P. gingivalis has been called a risk factor for Alzheimer’s disease (Kanagasingam et al., 2020). 

Cortexyme’s approach is based on the theory that P. gingivalis invades the brain, where gingipains contribute to Alzheimer’s pathology (see Sabbagh and Decourt, 2022). The company reported elevated gingipain in brain tissue from people with AD, and a correlation between levels of gingipain and tau proteins in postmortem middle temporal gyrus from AD and healthy control tissue. P. gingivalis DNA was detected in postmortem cortices from people with AD and healthy controls, and in CSF of AD patients (Jan 2019 news on Dominy et al., 2019). In the same study, they show that in mice, oral P. gingivalis infection led to the appearance of bacterial DNA in the brain, increased brain Aβ42 production, neuroinflammation, and hippocampal degeneration. The first three findings were reported to be reduced by atuzaginstat; results for hippocampal cell death were not reported.

In preclinical work from other labs, infection with P. gingivalis was reported to worsen AD pathology and cognitive impairment in AD transgenic mice, and to cause neuroinflammation, memory impairment, neurodegeneration, micro- and astrogliosis, increased brain Aβ and phospho-tau, and neurofibrillary tangles in wild-type C57Bl6 mice (Ishida et al., 2017Ilievski et al., 2018Ding et al., 2018). For a review of the preclinical literature, see Costa et al., 2021.

In human neurons grown in culture, P. gingivalis infection led to tau phosphorylation and degradation, synapse loss, and cell death (Haditsch et al., 2020).

P. gingivalis is associated with cardiovascular disease. In rabbits, oral infection was reported to increase arterial plaque and levels of the inflammatory marker CRP. Both were reversed by treatment with COR388 (2020 AAIC abstract). In aged dogs with periodontal disease, ninety days of COR388 reduced oral bacterial load and gum pathology (Arastu-Kapur et al., 2020). In addition, older dogs had bacterial antigens and ribosomal RNA in their brains, consistent with systemic infection seen in humans.

Findings

Two Phase 1 trials of atuzaginstat were completed by June 2019. In a single-dose study of 5 to 250 mg capsules in 34 healthy adults, the compound was safe and well-tolerated. A multiple-dose study assessed safety and tolerability in 24 healthy older adults (mean age of 60 years) and nine with AD (mean age 72). According to a company press release and a poster presentation at the 2018 CTAD conference, healthy adults received 25, 50, or 100 mg COR388 or placebo every 12 hours for 10 days; AD patients took 50 mg or placebo every 12 hours for 28 days. The pharmacokinetic profiles of COR388 in AD and controls were reported to be similar. All volunteers with AD had P. gingivalis DNA fragments in their CSF at baseline. COR388 caused no serious adverse reactions, and no one withdrew. Gingipains also were reported to degrade ApoE, and 28 days of treatment with COR388 was claimed to reduce CSF ApoE fragments (2020 AAIC abstract).

A Phase 2/3 trial (GAIN) evaluating a 48-week course of COR388 in 643 people with mild to moderate AD began in April 2019. Participants took either 40 mg, 80 mg, or placebo twice daily. The primary endpoint was to be ADAS-Cog11 score, and the ADCS-ADL was added later as a co-primary functional endpoint. Further outcomes included CDR-SB, MMSE, NPI, the Winterlight Speech Assessment, MRI brain scans, and change in periodontal disease status. Investigators assessed CSF Aβ and tau, plus P. gingivalis DNA and gingipains in CSF, blood, and saliva, before and after treatment. A dental substudy of 228 participants is assessing effects of COR388 on periodontal disease. This trial involves 93 sites in the U.S. and Europe. The U.S. sites are offering a 48-week open-label extension.

According to a presentation at the 2020 CTAD, GAIN was fully enrolled. At baseline, more than 80 percent of participants had CSF Aβ and tau levels consistent with amyloid positivity or an AD diagnosis. All had detectable antibodies to P. gingivalis in their blood. In the dental substudy, 90 percent had periodontal disease. In December 2020, an independent data-monitoring committee recommended continuing the trial after a planned futility analysis of 300 patients treated for six months (press release).

In February 2021, the FDA placed a partial clinical hold on GAIN because of liver abnormalities in some participants (press release). Dosing in the open-label extension was stopped, but the placebo-controlled portion of GAIN continued. Cortexyme characterized the liver effects as reversible and showing no risk of long-term effects.

In October 2021, Cortexyme announced top-line results indicating the trial had missed its co-primary endpoints of ADAS-Cog11 and ADCS-ADL (press release). The company reported a statistically significant 57 percent slowing of decline on the ADAS-Cog11 in a subgroup with detectable saliva P. gingivalis DNA at baseline who took the higher dose; a 42 percent slowing on the lower dose did not reach statistical significance. This prespecified subgroup analysis included 242 participants; it found no effect on the ADCS-ADL. Improvements in ADAS-Cog and other cognitive endpoints correlated with reductions in saliva P. gingivalis DNA, according to data presented at CTAD 2021 in November. The most common treatment-related adverse events were gastrointestinal, occurring in 12 to 15 percent of treated participants. The treatment groups had dose-related liver enzyme elevations greater than three times the upper limit of normal, in 7 and 15 percent of participants on low and high doses, respectively, with bilirubin elevation reported in two participants on the high dose. The elevations occurred mainly in the first six weeks of treatment, and all resolved without long-term effects. Discontinuations due to transaminase elevations numbered one on placebo, and five and 17 in the 40 mg and 80 mg groups, respectively. The overall dropout rate was 25 percent in the placebo group, and 40 percent in atuzaginstat groups. There were five deaths in the high dose arm, and one in the low dose. All were deemed unrelated to drug. There was no evidence of ARIA or other imaging abnormalities.

At CTAD, the company announced plans for a confirmatory trial, pending discussions with regulators. The plan was to test atuzaginstat in people with mild to moderate AD and evidence of P. gingivalis infection, at the lower dose of 40 mg twice daily, reached by titration to minimize liver effects. The company was also planning a trial in Parkinson’s disease to begin in 2022. These trials were never registered.

In September 2021, Cortexyme began a Phase 1 trial of a second-generation lysin-gingipain inhibitor, COR588 (press release). This compound is expected to require only once-daily dosing. Results were expected in May 2022.

In January 2022, the company announced that the FDA had placed a full clinical hold on atuzaginstat due to concerns about liver toxicity (press release). The company said it intended to develop its backup compound, COR588, for Alzheimer’s disease, pending Phase 1 results. In July 2022, Cortexyme announced that COR588 had met safety and tolerability endpoints in a single- and multiple-ascending dose study in healthy adults (press release).

In August 2022, Cortexyme discontinued the gingipain inhibitor program, and offered it for external licensing (press release). The company changed its name to Quince, and its focus to bone disease. In January 2023, Quince put out word that it had sold Cortexyme’s legacy small molecule protease inhibitor portfolio to Lighthouse Pharmaceuticals, a company co-founded by a former Cortexyme CEO (press release).

For all trials of atuzaginstat, see clinicaltrials.gov.

SCHEME

Patent

PATENT

WO2018053353

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018053353&_cid=P10-M1OFBK-46119-1

VIII. Examples

Example 1. Preparation of (S)-N-(7-amino-2-oxo-1-(2,3,6-trifluorophenoxy)heptan-3- yl)cyclopentanecarboxamide(1)hydrochloride

[0224] To a mixture of compound 1.4 (23.0 g, 67.2 mmol, 1.00 eq) in THF (200 mL) was added NMM (6.79 g, 67.2 mmol, 7.38 mL, 1.00 eq), isobutyl carbonochloridate (9.17 g, 67.2 mmol, 8.82 mL, 1.00 eq), and diazomethane (5.65 g, 134 mmol, 2.00 eq) at -40 °C under N2 (15 psi). The mixture was stirred at 0 °C for 30 min. LCMS showed the reaction was completed. FLO (200 mL) was added to the reaction and extracted with two 300-mL portions of ethyl acetate. The combined organic phase was washed with two 200-mL portions of brine (200, dried with anhydrous Na2SO4, filtered and concentrated under vacuum to provide crude compound 1.3 (30.0 g, crude) as a yellow oil.

[0225] To a mixture of compound 1.3 (20.0 g, 54.6 mmol, 1.00 eq) in EtOAc (300 mL) was

added hydrogen bromide(29.8 g, 121.7 mmol, 20.0 mL, 33% purity, 2.23 eq) at -20 °C under

N2 (15 psi). The mixture was stirred at -20 °C for 10 min. TLC (petroleum ether : ethyl

acetate = 0:1) showed the reaction was completed. The reaction was basified by addition of

saturated NaHCO3 until the pH of the mixture reached 8, and the mixture was extracted with

three 500-mL portions of EtOAc. The combined organic phase was washed with two 200-mL portions of brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum

to afford crude compound 1.2 (15.0 g, crude) as a yellow solid.

[0226] To a mixture of compound 1.2 (4.00 g, 9.54 mmol, 1.00 eq) in DMF (40.0 mL) was

added 2,6-difluorophenol (1.49 g, 11.4 mmol, 1.20 eq) and KF (1.66 g, 28.6 mmol, 670 μL,

3.00 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. TLC (petroleum ether: ethyl

acetate = 1:1) showed the reaction was completed. H2O (150 mL) was added to the mixture

and extracted with two 200-mL portions of ethyl acetate. The combined organic phase was

washed with two 100-mL portions of brine, dried with anhydrous Na2SO4, filtered, and

concentrated under vacuum. The residue was purified by silica gel chromatography

(petroleum ether: ethyl acetate = 100:1, 5:1) to afford compound 1.1 (2.50 g, 5.35 mmol,

56.1 % yield) as a yellow solid.

[0227] To a mixture of compound 1.1 (4.00 g, 8.22 mmol, 1.00 eq) in EtOAc (3.00 mL) was added HCl/EtOAc (40.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h. TLC (petroleum ether : ethyl acetate=2:1) showed the reaction was completed. The mixture was concentrated in reduced pressure to provide (.S)-N-(7-amino-2-oxo-1-(2,3,6-trifluorophenoxy)heptan-3-yl)cyclopentanecarboxamide 1 hydrochloride salt (1.34 g, 3.16 mmol) as a light yellow solid. LCMS (ESI): m/z: [M + H] calcd for C19H25N2F3O3: 387.2; found 387.1; RT=2.508 min. 1HNMR (400 MHz, DMSO-d6) δ ppm 1.21 – 1.83 (m, 15 H) 2.60 – 2.81 (m, 3 H) 4.30 (ddd, J=9.70, 7.17, 4.52 Hz, 1 H) 5.02 – 5.22 (m, 2 H) 7.12 – 7.24 (m, 2 H) 7.98 (br s, 3 H) 8.32 (d, J=7.28 Hz, 1 H).

Paper Citations

  1. Raha D, Broce S, Haditsch U, Rodriguez L, Ermini F, Detke M, Kapur S, Hennings D, Roth T, Nguyen M, Holsinger LJ, Lynch CC, Dominy SCOR388, a novel gingipain inhibitor, decreases fragmentation of APOE in the central nervous system of Alzheimer’s disease patients: AbstractAlzheimer’s & Dementia, 07 December 2020
  2. O’Brien-Simpson NM, Pathirana RD, Walker GD, Reynolds ECPorphyromonas gingivalis RgpA-Kgp proteinase-adhesin complexes penetrate gingival tissue and induce proinflammatory cytokines or apoptosis in a concentration-dependent mannerInfect Immun. 2009 Mar;77(3):1246-61. Epub 2008 Dec 29 PubMed.
  3. Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean SDetermining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissueJ Alzheimers Dis. 2013 Jan 1;36(4):665-77. PubMed.
  4. Kanagasingam S, Chukkapalli SS, Welbury R, Singhrao SKPorphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s DiseaseJ Alzheimers Dis Rep. 2020 Dec 14;4(1):501-511. PubMed.
  5. Sabbagh MN, Decourt BCOR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer diseaseExpert Opin Investig Drugs. 2022 Oct;31(10):987-993. Epub 2022 Sep 1 PubMed.
  6. Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, Nguyen M, Haditsch U, Raha D, Griffin C, Holsinger LJ, Arastu-Kapur S, Kaba S, Lee A, Ryder MI, Potempa B, Mydel P, Hellvard A, Adamowicz K, Hasturk H, Walker GD, Reynolds EC, Faull RL, Curtis MA, Dragunow M, Potempa JPorphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitorsSci Adv. 2019 Jan;5(1):eaau3333. Epub 2019 Jan 23 PubMed.
  7. Ishida N, Ishihara Y, Ishida K, Tada H, Funaki-Kato Y, Hagiwara M, Ferdous T, Abdullah M, Mitani A, Michikawa M, Matsushita KPeriodontitis induced by bacterial infection exacerbates features of Alzheimer’s disease in transgenic miceNPJ Aging Mech Dis. 2017;3:15. Epub 2017 Nov 6 PubMed.
  8. Ilievski V, Zuchowska PK, Green SJ, Toth PT, Ragozzino ME, Le K, Aljewari HW, O’Brien-Simpson NM, Reynolds EC, Watanabe KChronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type micePLoS One. 2018;13(10):e0204941. Epub 2018 Oct 3 PubMed.
  9. Ding Y, Ren J, Yu H, Yu W, Zhou YPorphyromonas gingivalis , a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in miceImmun Ageing. 2018;15:6. Epub 2018 Jan 30 PubMed.
  10. Costa MJ, de Araújo ID, da Rocha Alves L, da Silva RL, Dos Santos Calderon P, Borges BC, de Aquino Martins AR, de Vasconcelos Gurgel BC, Lins RDRelationship of Porphyromonas gingivalis and Alzheimer’s disease: a systematic review of pre-clinical studiesClin Oral Investig. 2021 Mar;25(3):797-806. Epub 2021 Jan 20 PubMed.
  11. Haditsch U, Roth T, Rodriguez L, Hancock S, Cecere T, Nguyen M, Arastu-Kapur S, Broce S, Raha D, Lynch CC, Holsinger LJ, Dominy SS, Ermini FAlzheimer’s Disease-Like Neurodegeneration in Porphyromonas gingivalis Infected Neurons with Persistent Expression of Active GingipainsJ Alzheimers Dis. 2020;75(4):1361-1376. PubMed.
  12. Ermini F, Rojas P, Dean A, Stephens D, Patel M, Haditsch U, Roth T, Rodriguez L, Broce S, Raha D, Nguyen M, Kapur S, Lynch CC, Dominy SS, Holsinger LJ, Hasturk HTargeting porphyromonas gingivalis to treat Alzheimer’s disease and comorbid cardiovascular disease: abstractAlzheimer’s & Dementia, 07 December 2020
  13. Arastu-Kapur S, Nguyen M, Raha D, Ermini F, Haditsch U, Araujo J, De Lannoy IA, Ryder MI, Dominy SS, Lynch C, Holsinger LJTreatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388Pharmacol Res Perspect. 2020 Feb;8(1):e00562. PubMed.

///////ATUZAGINSTAT, COR388, COR 388, Cortexyme, Quince Therapeutics

Vorbipiprant

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Vorbipiprant,

CR6086

1417742-86-9

4-[1-[[[(5R)-6-[[4-(Trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]oct-5-yl]carbonyl]amino]cyclopropyl]benzoic acid

Benzoic acid, 4-[1-[[[(5R)-6-[[4-(trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]oct-5-yl]carbonyl]amino]cyclopropyl]-

Molecular Weight472.50
FormulaC26H27F3N2O3

Vorbipiprant (CR6086) is an EP4 receptor antagonist, serving as a targeted immunomodulator. Thus, Vorbipiprant is also a potential immune checkpoint inhibitor, to turn cold tumors into hot tumors. Vorbipiprant also antagonizes PGE2-stimulated cAMP production (IC50=22 nM). Vorbipiprant exhibit striking DMARD effects in rodents, and anti-inflammatory activity to inhibt immune-mediated inflammatory diseases.

SCHEME

PATENT

Rottapharm S.p.A.

World Intellectual Property Organization, WO2013004290

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013004290&_cid=P10-M25P3U-15334-1

Example 7: 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid (single unknown enantiomer) (E7)

Procedure A:

The title compound (E7) (54 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from methyl 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D122b) (100mg). (LiOH: 4 eq; Reaction time: 18 hrs; RT)

MS: (ES/+) m/z: 473.4 [MH+] C26H27F3N2O3 requires 472.20

Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 18.97 min.

1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.97 (d, J = 8.0 Hz, 2 H), 7.74 – 7.35 (m, 5 H), 7.26 (br. s., 1 H), 3.86 (d, J = 14.1 Hz, 1 H), 3.38 (d, J = 14.1 Hz, 1 H), 3.08 (d, J = 7.8 Hz, 1 H), 2.91 (d, J = 9.8 Hz, 1 H), 2.27 (br. s., 1 H), 2.05 (t, J = 1 1 .2 Hz, 1 H), 1 .84 (br. s., 1 H), 1 .50 – 1 .24 (m, 4 H), 1 .14 (br. s., 1 H), 0.98 (d, J = 12.7 Hz, 1 H), 0.53 – 0.23 (m, 4 H)

Procedure B:

methyl 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D123)) (17.7 g, 36.38 mmol) was partitioned between dioxane (485 ml) and water (242 ml) prior addition of LiOH H2O (6.1 g,

145.5 mmol). The mixture was stirred at RT for 10 hrs. Water (200 ml) was added followed by addition of acetic acid (5.27 ml). Dioxane was evaporated off and acetic acid was added until the pH of the aqueous solution reached the value of ~ 4. The white solid was filtered from the reaction and dried under vacuum overnight then 24 hrs under vacuum at 40 °C affording the title compound (E7) (16.7g).

MS: (ES/+) m/z: 473.3 [MH+] C26H27F3N203 requires 472.20

Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 19.07 min.

1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.92 – 12.51 (m, 1 H), 8.83 – 8.62 (m, 1 H), 7.85 – 7.75 (m, 2 H), 7.74 – 7.57 (m, 4 H), 7.26 – 7.14 (m, 2 H), 3.87 – 3.72 (m, 1 H), 3.27 – 3.20 (m, 1 H), 2.99 – 2.86 (m, 1 H), 2.79 – 2.69 (m, 1 H), 2.19 – 1 .98 (m, 2 H), 1 .86 – 1 .70 (m, 1 H), 1 .32 – 1 .07 (m, 5 H), 0.94 – 0.82 (m, 1 H), 0.46 -0.17 (m, 4 H).


[1]. Caselli G, et al. Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug. Arthritis Res Ther. 2018 Mar 1;20(1):39.  [Content Brief][2]. Caselli G, et al. Combination of the EP4 antagonist CR6086 and anti-PD-1 monoclonal antibody inhibits tumor growth in a microsatellite stable colorectal cancer in mice[J]. Cancer Research, 2020, 80(16_Supplement): 2208-2208.

//////////Vorbipiprant, CR 6086


VICATERTIDE

$
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VICATERTIDE

1251838-01-3

L-Leucyl-L-glutaminyl-L-valyl-L-valyl-L-tyrosyl-L-leucyl-L-histidine

C42H66N10O10

L-Histidine, L-leucyl-L-glutaminyl-L-valyl-L-valyl-L-tyrosyl-L-leucyl- (ACI)

871.04

SB-01, HY-P5542, CS-0887146

(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-imidazol-5-yl)propanoic acid

  • L-Leucyl-L-glutaminyl-L-valyl-L-valyl-L-tyrosyl-L-leucyl-L-histidine (ACI)
  • 1: PN: KR983182 SEQID: 1 claimed sequence
  • Vevoctadekin
  • LQVVYLH

Vicatertide is a TGF beta-1 inhibitor[1].

KR983182 

SEQ ID NO: 1 (LQVVYLH: SEQ ID NO: 1)

<Example 1> Preparation of peptides

A peptide having the amino acid sequence of SEQ ID NO: 1 (LQVVYLH: SEQ ID NO: 1) was produced by Peptron Inc. Specifically, coupling was performed one by one starting from the C-terminus using the Fmoc SPPS (9-Fluorenylmethyloxycarbonyl solid phase peptide synthesis) method using an automatic synthesizer (ASP48S, Peptron Inc).

NH 2 -His(Trt)-2-chloro-Trityl Resin , in which the first amino acid at the C-terminus of the peptide was attached to the resin, was used. All amino acid raw materials used in peptide synthesis have the N-terminus protected by Fmoc, and all residues are trityl (Trt), t-butyloxycarbonyl (Boc), t-butyl (t-Bu), etc., which are removed by acid. The protected one was used. As a coupling reagent, HBTU (2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)/HOBt (Hydroxxybenzotriazole)/NMM (N-methylmorpholine) was used. (1) Protected amino acid (8 equivalents) and coupling reagent HBTU (8 equivalents)/HOBt (8 equivalents)/NMM (16 equivalents) were dissolved in DMF (Dimethylformamide) and added, followed by reaction at room temperature for 2 hours. (2) Fmoc removal was performed twice for 5 minutes at room temperature by adding 20% ​​piperidine in DMF. After repeating reactions (1) and (2) to create the basic peptide skeleton, TFA (trifluoroacetic acid)/EDT (1,2-ethanedithiol)/Thioanisole/TIS (triisopropylsilane)/H 2 O=90/ 2.5 / Peptides were separated from the resin using 2.5/2.5/2.5. After purification by reverse phase HPLC using a Vydac Everest C18 column (250 mm × 22 mm, 10 μm), water-acetonitrile linear gradient (10~75% ( v/v) of acetonitrile) method. The molecular weight of the purified peptide was confirmed using LC/MS (Agilent HP1100 series) and lyophilized.

Ref

[1]. WHO D rug Information. Vol. 37, No. 2, 2023.

////VICATERTIDE, SB-01, SB 01, HY P5542, CS 0887146

VALILTRAMIPROSATE

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VALILTRAMIPROSATE

1034190-08-3

  • (S)-3-(2-Amino-3-methylbutanamido)propane-1-sulfonic acid
  • BLU8499
  • WHO 11912
Molecular Weight238.30
FormulaC8H18N2O4S
CAS No.1034190-08-3

ALZ-801
Synonyms: valiltramiprosate, NRM-8499, homotaurine prodrug, 3-APS

This is a prodrug of homotaurine, a modified amino acid previously developed under the names tramiprosate and Alzhemed™. ALZ-801 is converted to homotaurine in vivo, but is more easily absorbed and lasts longer in the blood than tramiprosate.

Tramiprosate was reported to inhibit Aβ42 aggregation into toxic oligomers (Gervais et al., 2007Kocis et al., 2017). Both ALZ-801 and tramiprosate are metabolized to 3-sulfopranpanoic acid (3-SPA), which is normally found in brain and also inhibits Aβ42 aggregation (Hey et al., 2018). A more recent study found that homotaurine activates GABA receptors, and suggests an alternative mechanism of action for ALZ-801 (Meera et al., 2023).

After tramiprosate failed in Phase 3, its maker, NeuroChem, marketed it as a nutritional supplement. Years later, a subgroup analysis of the trial data indicated a potential positive effect in participants who carried two copies of ApoE4 (Abushakra et al., 2016Abushakra et al., 2017). Alzheon licensed ALZ-801 from NeuroChem and is developing it for Alzheimer’s disease.

ALZ-801 is a potent and orally available small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor, valine-conjugated proagent of Tramiprosate with substantially improved PK properties and gastrointestinal tolerability compared with the parent compound. ALZ-801 is an advanced and markedly improved candidate for the treatment of alzheimer’s disease.

SCHEME

REF 1

US20080146642

https://patents.google.com/patent/US20080146642A1/en

HCL WATER, Dowex™ Marathon™ C ion-exchange column

General/Typical Procedure: [0311] (i) The solid material was dissolved in water (25 mL). The solution was passed through a Dowex™ Marathon™ C ion-exchange column (strongly acidic, 110 g (5 eq), prewashed). The strong acidic fractions were combined and treated with concentrated HCl (10 mL). The mixture was stirred at 50° C. for 30 minutes, and then was concentrated to dryness. The residual material was co-evaporated with EtOH (ethanol) to completely remove water. EtOH (100 mL) was added to the residue. The mixture was stirred at reflux for 1 h, and then cooled to room temperature. The solid material was collected by filtration. The solid material was dissolved in water (10 mL). The solution was added drop wise to EtOH (100 mL). The product slowly crystallized. The suspension was stirred at room temperature for 30 minutes. The solid material was collected by filtration and it was dried in a vacuum oven (60° C.). ID A2. 1H NMR (D2O).δ. 0.87-0.90 (m, 6H), 1.83 (qt, J = 7.2 Hz, 2H), 2.02-2.09 (m, 1H), 2.79 (t, J = 7.8 Hz, 2H), 3.20-3.29 (m, 2H), 3.60 (d, J = 6.3 Hz, 2H); 13C NMR (D2O).δ. 17.20, 17.77, 24.11, 30.00, 38.29, 48.63, 58.96, 169.35; m/z 237 (M-1).

////////VALILTRAMIPROSATE, ALZ-801, ALZ 801, BLU 8499, WHO 11912

Avenciguat

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Avenciguat, 1579514-06-9

BI-685509, 582.7 g/mol, C34H38N4O5

UNII ZA7KTB4PSP

5-ethoxy-1-[6-[3-methyl-2-[[5-methyl-2-(oxan-4-yl)-3,4-dihydro-1H-isoquinolin-6-yl]methoxy]phenyl]pyridin-2-yl]pyrazole-4-carboxylic acid

Avenciguat (BI-685509) is a potent and orally active sGC activator. Avenciguat restores cyclic guanosine monophosphate (cGMP) and improves functionality of nitric oxide (NO) pathways. Avenciguat can be used in research of chronic kidney disease (CKD) and diabetic kidney disease (DKD).


Avenciguat is under investigation in clinical trial NCT05282121 (A Study to Test Whether BI 685509 Alone or in Combination With Empagliflozin Helps People With Liver Cirrhosis Caused by Viral Hepatitis or Non-alcoholic Steatohepatitis (NASH) Who Have High Blood Pressure in the Portal Vein (Main Vessel Going to the Liver)).

Avenciguat (development name BI 685509) is a soluble guanylate cyclase activator developed by Boehringer Ingelheim for kidney disease,[1][2] and cirrhosis.[3][4][5]

SCHEME

Ref

PAPER

Journal of Pharmacology and Experimental Therapeutics (2023), 384(3), 382-39

PATENT

Boehringer Ingelheim International GmbH

WO2014039434

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014039434&_cid=P12-M29UB4-37937-1

PATENT

US20230293513

WO2020011804

Clinical data
Other namesBI 685509
Legal status
Legal statusInvestigational
Identifiers
showIUPAC name
CAS Number1579514-06-9
PubChem CID89992620
UNIIZA7KTB4PSP
Chemical and physical data
FormulaC34H38N4O5
Molar mass582.701 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
References

^ Cherney, David Z. I.; de Zeeuw, Dick; Heerspink, Hiddo J. L.; Cardona, Jose; Desch, Marc; Wenz, Arne; Schulze, Friedrich; Nangaku, Masaomi (August 2023). “Safety, tolerability, pharmacodynamics and pharmacokinetics of the soluble guanylyl cyclase activator BI 685509 in patients with diabetic kidney disease: A randomized trial”Diabetes, Obesity and Metabolism25 (8): 2218–2226. doi:10.1111/dom.15099PMID 37232058S2CID 258909393.

^ Reinhart, Glenn A.; Harrison, Paul C.; Lincoln, Kathleen; Chen, Hongxing; Sun, Peng; Hill, Jon; Qian, Hu Sheng; McHugh, Mark C.; Clifford, Holly; Ng, Khing Jow; Wang, Hong; Fowler, Danielle; Gueneva-Boucheva, Kristina; Brenneman, Jehrod B.; Bosanac, Todd; Wong, Diane; Fryer, Ryan M.; Sarko, Chris; Boustany-Kari, Carine M.; Pullen, Steven S. (March 2023). “The Novel, Clinical-Stage Soluble Guanylate Cyclase Activator BI 685509 Protects from Disease Progression in Models of Renal Injury and Disease”Journal of Pharmacology and Experimental Therapeutics384 (3): 382–392. doi:10.1124/jpet.122.001423PMID 36507845S2CID 254387173.

^ Lawitz, Eric J.; Reiberger, Thomas; Schattenberg, Jörn M.; Schoelch, Corinna; Coxson, Harvey O.; Wong, Diane; Ertle, Judith (November 2023). “Safety and pharmacokinetics of BI 685509, a soluble guanylyl cyclase activator, in patients with cirrhosis: A randomized Phase Ib study”Hepatology Communications7 (11). doi:10.1097/HC9.0000000000000276PMC 10615399PMID 37889522.

^ Jones, Amanda K.; Chen, Hongxing; Ng, Khing Jow; Villalona, Jorge; McHugh, Mark; Zeveleva, Svetlana; Wilks, James; Brilisauer, Klaus; Bretschneider, Tom; Qian, Hu Sheng; Fryer, Ryan M. (July 2023). “Soluble Guanylyl Cyclase Activator BI 685509 Reduces Portal Hypertension and Portosystemic Shunting in a Rat Thioacetamide-Induced Cirrhosis Model”Journal of Pharmacology and Experimental Therapeutics386 (1): 70–79. doi:10.1124/jpet.122.001532PMID 37230799S2CID 258909514.

^ Reiberger, Thomas; Berzigotti, Annalisa; Trebicka, Jonel; Ertle, Judith; Gashaw, Isabella; Swallow, Ros; Tomisser, Andrea (24 April 2023). “The rationale and study design of two phase II trials examining the effects of BI 685509, a soluble guanylyl cyclase activator, on clinically significant portal hypertension in patients with compensated cirrhosis”Trials24 (1): 293. doi:10.1186/s13063-023-07291-3PMC 10123479PMID 37095557.

[1]. Reinhart GA, et, al. The Novel, Clinical-Stage Soluble Guanylate Cyclase Activator BI 685509 Protects from Disease Progression in Models of Renal Injury and Disease. J Pharmacol Exp Ther. 2023 Mar;384(3):382-392.  [Content Brief]

////////////Avenciguat, 1579514-06-9, BI 685509,

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