作者
Guanglin Luo,Ling Chen,Walter A. Kostich,Brian D. Hamman,Jason Allen,Amy Easton,Clotilde Bourin,Michael Gulianello,Jonathan Lippy,Susheel J. Nara,Tarun K. Maishal,Kamalraj Thiyagarajan,Prasadrao Jalagam,Sreenivasulu Naidu Pattipati,Kumaran Dandapani,Manoj Dokania,Pradeep Vattikundala,Vivek Sharma,Saravanan Elavazhagan,Manoj Kumar,Manish Lal Das,Santosh Wagh,Anand Balakrishnan,Benjamin M. Johnson,Kenneth S. Santone,George Thalody,Rex Denton,Hariharan Saminathan,Vinay K. Holenarsipur,Anoop Kumar,Abhijith Rao,Siva Prasad Putlur,Sarat Kumar Sarvasiddhi,Ganesh M. Shankar,Justin Vijay Louis,Manjunath Ramarao,Charles M. Conway,Yu-Wen Li,Rick L. Pieschl,Yuan Tian,Yang Hong,Jonathan L. Ditta,Arvind Mathur,Jianqing Li,Daniel P. Smith,Joseph Pawluczyk,Dawn Sun,Shiuhang Yip,Dauh‐Rurng Wu,Muthalagu Vetrichelvan,Anuradha Gupta,Alan Wilson,Suma Gopinathan,Suman Wason,Linda J. Bristow,Charles F. Albright,Joanne J. Bronson,John E. Macor,Carolyn D. Dzierba
摘要
Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. (S)-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 (34) showed excellent efficacy in two rodent neuropathic pain models and excellent central nervous system (CNS) penetration and target engagement at the spinal cord with an average brain to plasma ratio of 20 in rat. The compound exhibited favorable physicochemical and pharmacokinetic properties, had an acceptable preclinical toxicity profile, and was chosen for clinical trials. BMS-986176/LX9211 (34) completed phase I trials with good human pharmacokinetics and minimum adverse events and is currently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).