The synthesis and structure-activity relationships of 1,3-diaryl 1,2,4-(4H)-triazol-5-ones: a new class of calcium-dependent, large conductance, potassium (maxi-K) channel opener targeted for urge urinary incontinence.
A series of 1,3-diaryl 1,2,4-(4H)-triazol-5-ones was prepared and shown by electrophysiological analysis to activate a cloned maxi-K channel mSlo (or hSlo) expressed in Xenopus laevis oocytes. The effects of these structurally novel maxi-K channel openers on bladder contractile function were studied in vitro using isolated rat bladder strips pre-contracted with carbachol. Several 1,3-diaryl 1,2,4-(4H)-triazol-5-one derivatives were found to be potent smooth muscle relaxants but this activity did not completely correlate with maxi-K channel opening.
Hewawasam
Piyasena
P
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. hewawasp@bms.com
Erway
Matthew
M
Thalody
George
G
Weiner
Harvey
H
Boissard
Christopher G
CG
Gribkoff
Valentin K
VK
Meanwell
Nicholas A
NA
Lodge
Nicholas
N
Starrett
John E
JE
D000818:Animals; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects; D004594:Electrophysiology; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008297:Male; D051379:Mice; D008845:Microinjections; D008958:Models, Molecular; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000502:physiology; D009865:Oocytes / Q000187:drug effects* / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000378:metabolism; D014549:Urinary Incontinence / Q000188:drug therapy*; D014982:Xenopus laevis
D001391:Azo Compounds; D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D002217:Carbachol; D002118:Calcium