Structure−Activity Studies of Novel Cyanoguanidine ATP-Sensitive Potassium Channel Openers for the Treatment of Overactive Bladder

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}-substituted benzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarized human bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP). These compounds were also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model of overactive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pig model of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oral bioavailability and a t 1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.