Structure-activity studies of novel cyanoguanidine ATP-sensitive potassium channel openers for the treatment of overactive bladder.

Abstract	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 t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.
Authors	Arturo Perez-Medrano, Michael E Brune, Steven A Buckner, Michael J Coghlan, Thomas A Fey, Murali Gopalakrishnan, Robert J Gregg, Michael E Kort, Victoria E Scott, James P Sullivan, Kristi L Whiteaker, William A Carroll
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 24 Pg. 6265-73 (Nov 29 2007) ISSN: 0022-2623 [Print] United States
PMID	17973362 (Publication Type: Journal Article)
Chemical References	4-chloro-N-(2,2-dichloro-1-(N'-(6-chloropyridin-3-yl)-N''-cyanoguanidino)propyl)benzamide Benzamides Guanidines KATP Channels Kir6.2 channel Potassium Channels, Inwardly Rectifying
Topics	Administration, Oral Animals Benzamides (chemical synthesis, pharmacokinetics, pharmacology) Biological Availability Crystallography, X-Ray Dogs Electric Stimulation Female Guanidines (chemical synthesis, pharmacokinetics, pharmacology) Humans In Vitro Techniques Ion Channel Gating KATP Channels (agonists, physiology) Muscle Relaxation Muscle, Smooth (drug effects, physiology) Potassium Channels, Inwardly Rectifying (agonists, physiology) Structure-Activity Relationship Swine Urinary Bladder (cytology, drug effects, physiology) Urinary Bladder, Overactive (drug therapy, physiopathology) Urodynamics

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