磺胺类药物作为选择性Na1.7抑制剂：优化效力和药代动力学以实现体内靶点作用。
Sulfonamides as Selective Na1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement.
作者信息
Marx Isaac E, Dineen Thomas A, Able Jessica, Bode Christiane, Bregman Howard, Chu-Moyer Margaret, DiMauro Erin F, Du Bingfan, Foti Robert S, Fremeau Robert T, Gao Hua, Gunaydin Hakan, Hall Brian E, Huang Liyue, Kornecook Thomas, Kreiman Charles R, La Daniel S, Ligutti Joseph, Lin Min-Hwa Jasmine, Liu Dong, McDermott Jeff S, Moyer Bryan D, Peterson Emily A, Roberts Jonathan T, Rose Paul, Wang Jean, Youngblood Beth D, Yu Violeta, Weiss Matthew M
机构信息
Department of Medicinal Chemistry, Department of Molecular Engineering, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Biologics, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
出版信息
ACS Med Chem Lett. 2016 Sep 21;7(12):1062-1067. doi: 10.1021/acsmedchemlett.6b00243. eCollection 2016 Dec 8.
Human genetic evidence has identified the voltage-gated sodium channel Na1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide as a potent and selective inhibitor of Na1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log ) while maintaining Na1.7 potency led to the identification of quinazoline (AM-2099). Compound demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.
人类遗传学证据已确定电压门控钠通道Na1.7是治疗疼痛的一个有吸引力的靶点。我们最初鉴定出萘磺酰胺是Na1.7的一种强效且选择性的抑制剂。通过平衡亲水性和疏水性（Log）以减少胆汁清除率同时保持Na1.7活性进行优化，从而鉴定出喹唑啉（AM - 2099）。化合物在大鼠和犬中表现出良好的药代动力学特征，并且在口服给药后的小鼠行为模型中显示出组胺诱导的搔抓发作的剂量依赖性降低。
Zotero 插件