Vrudhula Vivekananda M, Dasgupta Bireshwar, Boissard Christopher G, Gribkoff Valentin K, Santone Kenneth S, Dalterio Richard A, Lodge Nicholas J, Starrett John E
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
Bioorg Med Chem Lett. 2005 Oct 1;15(19):4286-90. doi: 10.1016/j.bmcl.2005.06.056.
Quinolinone 1 is a potent maxi-K potassium channel opener. In an effort to design analogs of 1 with a better inhibitory profile toward the CYP2C9 isozyme, the two acidic sites were chemically modified independently to generate a number of analogs. These analogs were evaluated as maxi-K channel openers in vitro using Xenopus laevis oocytes expressing cloned hSlo maxi-K channels. Compounds 15, 17, and 19 showed potent activity as maxi-K channel openers and were further evaluated for inhibition of the activity of the CYP2C9 isozyme. Compounds 17 and 19 showed diminished inhibitory potency against 2C9 and also against a panel of other more common CYP isozymes.
喹啉酮1是一种强效的大电导钙激活钾通道（maxi-K）开放剂。为了设计出对CYP2C9同工酶具有更好抑制特性的1的类似物，对两个酸性位点进行了独立的化学修饰，以生成许多类似物。使用表达克隆的hSlo大电导钙激活钾通道的非洲爪蟾卵母细胞，在体外将这些类似物评估为大电导钙激活钾通道开放剂。化合物15、17和19表现出作为大电导钙激活钾通道开放剂的强效活性，并进一步评估了它们对CYP2C9同工酶活性的抑制作用。化合物17和19对2C9以及一组其他更常见的CYP同工酶的抑制效力降低。
