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.JM
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).
Links
Pub Type(s)
Journal Article
Language
eng
PubMed ID
35257579
Citation
Luo, Guanglin, et al. "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." Journal of Medicinal Chemistry, vol. 65, no. 6, 2022, pp. 4457-4480.
Luo G, Chen L, Kostich WA, et al. 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;65(6):4457-4480.
Luo, G., Chen, L., Kostich, W. A., Hamman, B., Allen, J., Easton, A., Bourin, C., Gulianello, M., Lippy, J., Nara, S., Maishal, T. K., Thiyagarajan, K., Jalagam, P., Pattipati, S. N., Dandapani, K., Dokania, M., Vattikundala, P., Sharma, V., Elavazhagan, S., ... Dzierba, C. D. (2022). 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. Journal of Medicinal Chemistry, 65(6), 4457-4480. https://doi.org/10.1021/acs.jmedchem.1c02131
Luo G, et al. 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 03 24;65(6):4457-4480. PubMed PMID: 35257579.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR
T1 - 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.
AU - Luo,Guanglin,
AU - Chen,Ling,
AU - Kostich,Walter A,
AU - Hamman,Brian,
AU - Allen,Jason,
AU - Easton,Amy,
AU - Bourin,Clotilde,
AU - Gulianello,Michael,
AU - Lippy,Jonathan,
AU - Nara,Susheel,
AU - Maishal,Tarun Kumar,
AU - Thiyagarajan,Kamalraj,
AU - Jalagam,Prasadrao,
AU - Pattipati,Sreenivasulu Naidu,
AU - Dandapani,Kumaran,
AU - Dokania,Manoj,
AU - Vattikundala,Pradeep,
AU - Sharma,Vivek,
AU - Elavazhagan,Saravanan,
AU - Verma,Manoj Kumar,
AU - Das,Manish Lal,
AU - Wagh,Santosh,
AU - Balakrishnan,Anand,
AU - Johnson,Benjamin M,
AU - Santone,Kenneth S,
AU - Thalody,George,
AU - Denton,Rex,
AU - Saminathan,Hariharan,
AU - Holenarsipur,Vinay K,
AU - Kumar,Anoop,
AU - Rao,Abhijith,
AU - Putlur,Siva Prasad,
AU - Sarvasiddhi,Sarat Kumar,
AU - Shankar,Ganesh,
AU - Louis,Justin V,
AU - Ramarao,Manjunath,
AU - Conway,Charles M,
AU - Li,Yu-Wen,
AU - Pieschl,Rick,
AU - Tian,Yuan,
AU - Hong,Yang,
AU - Ditta,Jonathan,
AU - Mathur,Arvind,
AU - Li,Jianqing,
AU - Smith,Daniel,
AU - Pawluczyk,Joseph,
AU - Sun,Dawn,
AU - Yip,Shiuhang,
AU - Wu,Dauh-Rurng,
AU - Vetrichelvan,Muthalagu,
AU - Gupta,Anuradha,
AU - Wilson,Alan,
AU - Gopinathan,Suma,
AU - Wason,Suman,
AU - Bristow,Linda,
AU - Albright,Charles F,
AU - Bronson,Joanne J,
AU - Macor,John E,
AU - Dzierba,Carolyn D,
Y1 - 2022/03/08/
PY - 2022/3/9/pubmed
PY - 2022/5/7/medline
PY - 2022/3/8/entrez
SP - 4457
EP - 4480
JF - Journal of medicinal chemistry
JO - J Med Chem
VL - 65
IS - 6
N2 - 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).
SN - 1520-4804
UR - https://www.unboundmedicine.com/medline/citation/35257579/Discovery_of_
DB - PRIME
DP - Unbound Medicine
ER -
