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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.
Luo, Guanglin; Chen, Ling; Kostich, Walter A; Hamman, Brian; Allen, Jason; Easton, Amy; Bourin, Clotilde; Gulianello, Michael; Lippy, Jonathan; Nara, Susheel; Maishal, Tarun Kumar; Thiyagarajan, Kamalraj; Jalagam, Prasadrao; Pattipati, Sreenivasulu Naidu; Dandapani, Kumaran; Dokania, Manoj; Vattikundala, Pradeep; Sharma, Vivek; Elavazhagan, Saravanan; Verma, Manoj Kumar; Das, Manish Lal; Wagh, Santosh; Balakrishnan, Anand; Johnson, Benjamin M; Santone, Kenneth S; Thalody, George; Denton, Rex; Saminathan, Hariharan; Holenarsipur, Vinay K; Kumar, Anoop; Rao, Abhijith; Putlur, Siva Prasad; Sarvasiddhi, Sarat Kumar; Shankar, Ganesh; Louis, Justin V; Ramarao, Manjunath; Conway, Charles M; Li, Yu-Wen; Pieschl, Rick; Tian, Yuan; Hong, Yang; Ditta, Jonathan; Mathur, Arvind; Li, Jianqing; Smith, Daniel; Pawluczyk, Joseph; Sun, Dawn; Yip, Shiuhang; Wu, Dauh-Rurng; Vetrichelvan, Muthalagu.
Afiliação
  • Luo G; Department of Neuroscience Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Chen L; Department of Neuroscience Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Kostich WA; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Hamman B; Lexicon Pharmaceuticals, 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
  • Allen J; Lexicon Pharmaceuticals, 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
  • Easton A; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Bourin C; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Gulianello M; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Lippy J; Department of Lead Evaluation, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Nara S; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Maishal TK; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Thiyagarajan K; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Jalagam P; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Pattipati SN; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Dandapani K; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Dokania M; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Vattikundala P; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Sharma V; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Elavazhagan S; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Verma MK; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Das ML; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Wagh S; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Balakrishnan A; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Johnson BM; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Santone KS; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Thalody G; Discovery Toxicology, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Denton R; Discovery Toxicology, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Saminathan H; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Holenarsipur VK; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Kumar A; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Rao A; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Putlur SP; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Sarvasiddhi SK; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Shankar G; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Louis JV; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Ramarao M; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • Conway CM; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Li YW; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Pieschl R; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Tian Y; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Hong Y; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Ditta J; Department of Neuroscience Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Mathur A; Department of Discovery Synthesis, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Li J; Department of Discovery Synthesis, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Smith D; Department of Discovery Synthesis, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Pawluczyk J; Department of Discovery Synthesis, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Sun D; Department of Discovery Synthesis, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Yip S; Department of Discovery Synthesis, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Wu DR; Department of Discovery Synthesis, Bristol-Myers Squibb Company, Route 206 and Province Line Rd, Princeton, New Jersey 08543, United States.
  • Vetrichelvan M; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 and 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
J Med Chem ; 65(6): 4457-4480, 2022 03 24.
Article em En | MEDLINE | ID: mdl-35257579
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aminas / Neuralgia Tipo de estudo: Risk_factors_studies Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aminas / Neuralgia Tipo de estudo: Risk_factors_studies Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos