Analogs Of A Potent Maxi-K Potassium Channel Opener With An Improved Inhibitory Profile Toward Cytochrome P450 Isozymes

Quinolinone 1 is a potent maxi-K potassium channel opener. In an effort to design analogs of I 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. (c) 2005 Elsevier Ltd. All rights reserved.