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

Guanglin 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 VermaManish 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

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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).

Original languageEnglish
Pages (from-to)4457-4480
Number of pages24
JournalJournal of Medicinal Chemistry
Volume65
Issue number6
DOIs
Publication statusPublished - Mar 24 2022
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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