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

  • J Med Chem. 2022 Mar 24;65(6):4457-4480. doi: 10.1021/acs.jmedchem.1c02131.
Guanglin Luo  1 ,  Ling Chen  1 ,  Walter A Kostich  2 ,  Brian Hamman  3 ,  Jason Allen  3 ,  Amy Easton  2 ,  Clotilde Bourin  2 ,  Michael Gulianello  2 ,  Jonathan Lippy  4 ,  Susheel Nara  5 ,  Tarun Kumar Maishal  5 ,  Kamalraj Thiyagarajan  5 ,  Prasadrao Jalagam  5 ,  Sreenivasulu Naidu Pattipati  5 ,  Kumaran Dandapani  5 ,  Manoj Dokania  5 ,  Pradeep Vattikundala  5 ,  Vivek Sharma  5 ,  Saravanan Elavazhagan  5 ,  Manoj Kumar Verma  5 ,  Manish Lal Das  5 ,  Santosh Wagh  5 ,  Anand Balakrishnan  6 ,  Benjamin M Johnson  6 ,  Kenneth S Santone  6 ,  George Thalody  7 ,  Rex Denton  7 ,  Hariharan Saminathan  5 ,  Vinay K Holenarsipur  5 ,  Anoop Kumar  5 ,  Abhijith Rao  5 ,  Siva Prasad Putlur  5 ,  Sarat Kumar Sarvasiddhi  5 ,  Ganesh Shankar  5 ,  Justin V Louis  5 ,  Manjunath Ramarao  5 ,  Charles M Conway  2 ,  Yu-Wen Li  2 ,  Rick Pieschl  2 ,  Yuan Tian  2 ,  Yang Hong  2 ,  Jonathan Ditta  1 ,  Arvind Mathur  8 ,  Jianqing Li  8 ,  Daniel Smith  8 ,  Joseph Pawluczyk  8 ,  Dawn Sun  8 ,  Shiuhang Yip  8 ,  Dauh-Rurng Wu  8 ,  Muthalagu Vetrichelvan  5 ,  Anuradha Gupta  5 ,  Alan Wilson  3 ,  Suma Gopinathan  3 ,  Suman Wason  3 ,  Linda Bristow  2 ,  Charles F Albright  2 ,  Joanne J Bronson  1 ,  John E Macor  1 ,  Carolyn D Dzierba  1
Affiliations
  • 1. Department of Neuroscience Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 2. Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 3. Lexicon Pharmaceuticals, 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
  • 4. Department of Lead Evaluation, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • 5. Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • 6. Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 7. Discovery Toxicology, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • 8. Department of Discovery Synthesis, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
PMID: 35257579 DOI: 10.1021/acs.jmedchem.1c02131
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).

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