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 t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.
Perez-Medrano
Arturo
A
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6104, USA. arturo.perezmedrano@abbott.com
Brune
Michael E
ME
Buckner
Steven A
SA
Coghlan
Michael J
MJ
Fey
Thomas A
TA
Gopalakrishnan
Murali
M
Gregg
Robert J
RJ
Kort
Michael E
ME
Scott
Victoria E
VE
Sullivan
James P
JP
Whiteaker
Kristi L
KL
Carroll
William A
WA
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D006146:Guanidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D054086:KATP Channels / Q000819:agonists / Q000502:physiology*; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists / Q000502:physiology; D013329:Structure-Activity Relationship; D013552:Swine; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000503:physiopathology; D014563:Urodynamics; D000099161:Kcnj11 Channel
D001549:Benzamides; D006146:Guanidines; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel; C526822:4-chloro-N-(2,2-dichloro-1-(N'-(6-chloropyridin-3-yl)-N''-cyanoguanidino)propyl)benzamide