Discovery of (S)‑1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine
(BMS-986176/LX-9211): A Highly Selective, CNS Penetrable, and Orally
Active Adaptor Protein‑2 Associated Kinase 1 Inhibitor in Clinical
Trials for the Treatment of Neuropathic Pain
posted on 2022-03-08, 13:04authored byGuanglin Luo, Ling Chen, Walter A. Kostich, Brian Hamman, Jason Allen, Amy Easton, Clotilde Bourin, Michael Gulianello, Jonathan Lippy, Susheel Nara, Tarun Kumar Maishal, Kamalraj Thiyagarajan, Prasadrao Jalagam, Sreenivasulu Naidu Pattipati, Kumaran Dandapani, Manoj Dokania, Pradeep Vattikundala, Vivek Sharma, Saravanan Elavazhagan, Manoj Kumar Verma, 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 Shankar, Justin V. Louis, Manjunath Ramarao, Charles M. Conway, Yu-Wen Li, Rick Pieschl, Yuan Tian, Yang Hong, Jonathan Ditta, Arvind Mathur, Jianqing Li, Daniel Smith, Joseph Pawluczyk, Dawn Sun, Shiuhang Yip, Dauh-Rurng Wu, Muthalagu Vetrichelvan, Anuradha Gupta, Alan Wilson, Suma Gopinathan, Suman Wason, Linda Bristow, Charles F. Albright, Joanne J. Bronson, John E. Macor, Carolyn D. Dzierba
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).