GSK2606414 is an orally available, potent, and selective PERK inhibitor

GSK2606414

1-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)indolin-1-yl)-2-(3-(trifluoromethyl)phenyl)ethanone

1-[5-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)indolin-1-yl]-2-(3-trifluoromethylphenyl)ethanone

CAS: 1337531-36-8

 Formula: C24H20F3N5O
Exact Mass: 451.16199

Glaxosmithkline Llc  innovator

CS-1428, QC-9698, GSK 2606414, KB-145925, GSK2606414|1337531-36-8|GSK-2606414

  nmr       ………http://www.medkoo.com/Product-Data/GSK2606414/GSK2606414-QC-APC40116Web.pdf

GSK2606414  is an orally available, potent, and selective PERK inhibitor. GSK2606414 inhibits PERK activation in cells and inhibits the growth of a human tumor xenograft in mice. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated in response to a variety of endoplasmic reticulum stresses implicated in numerous disease states. Evidence that PERK is implicated in tumorigenesis and cancer cell survival stimulated our search for small molecule inhibitors. (12/13/2013).

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The chemical structures of GSK2606414  and GSK2656157 are very similar. The following graphic is a side-by-side comparison.

GSK2606414 is a drug which is the first selective inhibitor discovered for the enzyme protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which is involved in various processes relating to cancer and neurodegenerative disorders. GSK2606414 was found to be a potent and selective inhibitor of PERK, with good oral bioavailability and blood-brain barrier penetration.^[1] PERK mediates the unfolded protein response pathway which is involved in the initiation of protein synthesis, and this pathway has been implicated in the neurotoxicity of various diseases including prion and Alzheimer’s diseases. Treatment with GSK2606414 was found to be neuroprotective in mice against damage caused by prions, and prevented the development of cognitive deficits and other clinical manifestations of prion disease. Extension of lifespan in treated mice was, however, not recorded. However, side effects such as weight loss and elevated blood glucose levels were also observed, likely due to unwanted inhibition of PERK in the pancreas gland, where it is involved in regulating insulin production.^[2]

WO 2011119663

http://www.google.com/patents/WO2011119663A1?cl=en

Example 35

5-{1 -[(3-fluorophenyl)acetyl]-2,3-dihydro-1 H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3- d]pyrimidin-4-amine

In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1 H-indol-5-yl)-7-methyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine2HCI (70.6 mg, 0.209 mmol), (3-fluorophenyl)acetic acid (32.2 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig’s base (0.146 mL, 0.836 mmol). The mixture was stirred at rt for over night. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The solid was filtered and dried to afford a white solid as the product. ¹H NMR (400 MHz, DMSO- cfe) δ ppm 3.23 (t, J=8.46 Hz, 2 H), 3.73 (s, 3 H), 3.92 (s, 2 H), 4.19 – 4.26 (m, 2 H), 7.08 – 7.1 1 (m, 1 H), 7.12 – 7.17 (m, 2 H), 7.23 (d, J=8.34 Hz, 1 H), 7.25 (s, 1 H), 7.31 (s, 1 H), 7.36 (s, 1 H), 7.39 (d, J=6.82 Hz, 1 H), 8.10 – 8.17 (m, 2 H).

References

1: Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA,  Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumar R, Hong X, Goetz A, Stanley T, Taylor JD, Sigethy SD, Tomberlin GH, Hassell AM, Kahler KM, Shewchuk LM, Gampe RT. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem. 2012 Aug 23;55(16):7193-207. doi: 10.1021/jm300713s. Epub 2012 Aug 8. PubMed PMID: 22827572

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