Discovery of (S)-1-((2 ',6-Bis(difluoromethyl)-[2,4 '-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211): AHighly Selective, CNS Penetrable, and Orally Active AdaptorProtein-2 Associated Kinase 1 Inhibitor in Clinical Trials for theTreatment of Neuropathic Pain

Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treatingneuropathic 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 identi-fied 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 andtarget 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 iscurrently in phase II clinical trials for diabetic peripheral neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) andpostherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281)