（）-1-（（2'，6-双（二氟甲基）-[2,4'-联吡啶]-5-基）氧基）-2,4-二甲基戊烷-2-胺（BMS-986176/LX-9211）的发现：一种高度选择性、可穿透中枢神经系统且口服活性的衔接蛋白2相关激酶1抑制剂，用于治疗神经性疼痛的临床试验。
Discovery of ()-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.
作者信息
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, Gupta Anuradha, Wilson Alan, Gopinathan Suma, Wason Suman, Bristow Linda, Albright Charles F, Bronson Joanne J, Macor John E, Dzierba Carolyn D
机构信息
Department of Neuroscience Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
出版信息
J Med Chem. 2022 Mar 24;65(6):4457-4480. doi: 10.1021/acs.jmedchem.1c02131. Epub 2022 Mar 8.
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. ()-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) () was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers. BMS-986176/LX9211 () 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 () 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).
最近的小鼠基因敲除研究确定衔接蛋白2相关激酶1（AAK1）是治疗神经性疼痛的一个可行靶点。已鉴定出AAK1的强效小分子抑制剂，其在各种啮齿动物疼痛模型中显示出疗效。（）-1-（（2'，6-双（二氟甲基）-[2,4'-联吡啶]-5-基）氧基）-2,4-二甲基戊-2-胺（BMS-986176/LX-9211）（）是从一类新型的双（杂）芳基醚中鉴定出的一种高度选择性、可穿透中枢神经系统的强效AAK1抑制剂。BMS-986176/LX9211（）在两种啮齿动物神经性疼痛模型中显示出优异的疗效，并且在脊髓具有出色的中枢神经系统（CNS）穿透性和靶点结合能力，在大鼠中的平均脑血浆比为20。该化合物具有良好的理化性质和药代动力学特性，具有可接受的临床前毒性特征，并被选入临床试验。BMS-986176/LX9211（）已完成I期试验，具有良好的人体药代动力学且不良事件最少，目前正在进行II期临床试验，用于治疗糖尿病性周围神经病变（ClinicalTrials.gov标识符：NCT04455633）和带状疱疹后神经痛（ClinicalTrials.gov标识符：NCT04662281）。
Zotero 插件