Discovery and Optimization of Biaryl Alkyl Ethers as a Novel Class of Highly Selective, CNS-Penetrable, and Orally Active Adaptor Protein-2-Associated Kinase 1 (AAK1) Inhibitors for the Potential Treatment of Neuropathic Pain.

Autor:	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 & Province Line Rd, Princeton, New Jersey 08543, United States., Nara S; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 & 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 & 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 & 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 & 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 & 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 & 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 & 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 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India., Lal Das M; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 & 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 & 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 & Province Line Rd, Princeton, New Jersey 08543, United States., Denton R; Discovery Toxicology, Bristol Myers Squibb Company, Route 206 & Province Line Rd, Princeton, New Jersey 08543, United States., Saminathan H; Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 & 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 & 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 & 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 & 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 & 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 & 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 & 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 & 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 & 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., Bristow L; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Albright CF; Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Bronson JJ; Department of Neuroscience Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Macor JE; Department of Neuroscience Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States., Dzierba CD; Department of Neuroscience Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Mar 24; Vol. 65 (6), pp. 4534-4564. Date of Electronic Publication: 2022 Mar 09.
DOI:	10.1021/acs.jmedchem.1c02132
Abstrakt:	Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 ( 4 ), as a highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced into phase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be highly selective and potent AAK1 inhibitors with good druglike properties. Among these, compounds 43 and 58 showed very good efficacy in two neuropathic pain rat models and had excellent CNS penetration and spinal cord target engagement. Both compounds also exhibited favorable physicochemical and oral pharmacokinetic (PK) properties. Compound 58 , a central pyridine isomer of BMS-986176/LX-9211 ( 4 ), was 4-fold more potent than 4 in vitro and showed lower plasma exposure needed to achieve similar efficacy compared to 4 in the CCI rat model. However, both 43 and 58 showed an inferior preclinical toxicity profile compared to 4 .
Databáze:	MEDLINE
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