文摘
A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N'-cyanoguanidines furnished N-{2,2-dichloro-1-[N'-(substituted-pyridin-3-yl)-N''-cyanoguanidino]propyl}-substitutedbenzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarizedhuman bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP). These compoundswere also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model ofoveractive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pigmodel of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oralbioavailability and a t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents arediscussed.