Design and synthesis of novel cyanoguanidine ATP-sensitive potassium channel openers for the treatment of overactive bladder.
Thiourea derivatives were identified as glyburide-reversible potassium channel openers through high-throughput screening. Based on these findings, a number of novel cyanoguanidines were designed and synthesized, which hyperpolarized human bladder K(ATP) channels. These agents are potent full agonists in relaxing electrically-stimulated pig bladder strips. The synthesis, SAR and biological properties of these agents are discussed.
Perez-Medrano
Arturo
A
Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA. arturo.perezmedrano@abbott.com
Buckner
Steven A
SA
Coghlan
Michael J
MJ
Gregg
Robert J
RJ
Gopalakrishnan
Murali
M
Kort
Michael E
ME
Lynch
John K
JK
Scott
Victoria E
VE
Sullivan
James P
JP
Whiteaker
Kristi L
KL
Carroll
William A
WA
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D015195:Drug Design; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001745:Urinary Bladder Diseases / Q000188:drug therapy* / Q000378:metabolism
D006146:Guanidines; D015221:Potassium Channels; D000255:Adenosine Triphosphate; C004711:dicyandiamido