6d22

Publication Abstract from PubMed

Tropomyosin receptor kinases are a family of three tyrosine kinases (TrkA, TrkB, TrkC) activated by peptide hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4). The NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain. In turn, this has led to significant interest in the development of small molecule inhibitors of TrkA as an alternative intervention point on the NGF pathway. However, recent reports have demonstrated the challenge of achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode. In this case Type III or Type IV allosteric inhibitors present a more promising selectivity design approach. In addition to subtype selectivity, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile for chronic, non-life threatening pain indications. Herein we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious and well-tolerated series of allosteric TrkA inhibitors. The use of SBDD methodologies such as docking analysis, crystallographic water analysis, and protein-ligand interaction analysis led to the rapid optimization of potency and lipophilic efficiency. Furthermore, introducing P-gp and BCRP efflux transporter activity combined with reducing intestinal metabolism liability allowed for chemical equity having a good absorption profile and culminated in the delivery of candidate quality compound 23.

Discovery of Allosteric, Potent, Subtype Selective and Peripherally Restricted TrkA Kinase Inhibitors.,Bagal SK, Omoto K, Blakemore DC, Bungay PJ, Bilsland JG, Clarke PJ, Corbett MS, Cronin CN, Cui JJ, Dias R, Flanagan NJ, Greasley SE, Grimley R, Johnson E, Fengas D, Kitching L, Kraus ML, McAlpine I, Nagata A, Waldron GJ, Warmus JS J Med Chem. 2018 Apr 19. doi: 10.1021/acs.jmedchem.8b00280. PMID:29672039^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.