Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors

Bagal, Sharan K.; Omoto, Kiyoyuki; Blakemore, David C.; Bungay, Peter J.; Bilsland, James G.; Clarke, Philip J.; Corbett, Matthew S.; Cronin, Ciaran N.; Cui, J. Jean; Dias, Rebecca; Flanagan, Neil J.; Greasley, Samantha E.; Grimley, Rachel; Johnson, Eric; Fengas, David; Kitching, Linda; Kraus, Michelle L.; McAlpine, Indrawan; Nagata, Asako; Waldron, Gareth J.; Warmus, Joseph S.

doi:10.1021/acs.jmedchem.8b00280

Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors

Journal Article · Thu Apr 19 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b00280· OSTI ID:1544827

^[1]; Omoto, Kiyoyuki ^[1]; Blakemore, David C. ^[1]; Bungay, Peter J. ^[1]; Bilsland, James G. ^[1]; Clarke, Philip J. ^[2]; Corbett, Matthew S. ^[3]; Cronin, Ciaran N. ^[4]; Cui, J. Jean ^[4]; Dias, Rebecca ^[1]; Flanagan, Neil J. ^[1]; Greasley, Samantha E. ^[4]; Grimley, Rachel ^[1]; Johnson, Eric ^[4]; Fengas, David ^[2]; Kitching, Linda ^[1]; Kraus, Michelle L. ^[4]; McAlpine, Indrawan ^[4]; Nagata, Asako ^[4]; Waldron, Gareth J. ^[1] more »

Pfizer Global R&D U.K., Cambridge (United Kingdom)
Peakdale Molecular, Sandwich, Kent (United Kingdom)
Pfizer Global R&D, Groton, CT (United States)
Pfizer Global R&D, San Diego, CA (United States)

Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Furthermore, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE

OSTI ID:: 1544827

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 1 Vol. 62; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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