Synthesis and potassium channel opening activity of substituted 10H-benzo[4,5]furo[3,2-b]indole-and 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids.
Compounds in a structurally novel series of substituted 10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acids and related 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids were prepared and shown to possess potent, bladder-selective smooth muscle relaxant properties and thus are potentially useful for the treatment of urge urinary incontinence. Electrophysiological studies using rat detrusor myocytes have demonstrated that prototype compound 7 produces a significant increase in hyperpolarizing current, which is iberiotoxin (IbTx)-reversed, thus consistent with activation of the large-conductance Ca(2+)-activated potassium channel (BK(Ca)).
Butera
J A
JA
Medicinal Chemistry, Chemical Sciences, Wyeth-Ayerst Research, CN 8000, Princeton, NJ 08543, USA. buteraj@war.wyeth.com
Antane
S A
SA
Hirth
B
B
Lennox
J R
JR
Sheldon
J H
JH
Norton
N W
NW
Warga
D
D
Argentieri
T M
TM
D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009132:Muscles / Q000166:cytology / Q000187:drug effects; D010276:Parasympatholytics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists / Q000378:metabolism*; D051381:Rats
C435603:10H-benzo(4,5)furo(3,2-b)indole-1-carboxylic acid; C435604:5,10-dihydro-indeno(1,2-b)indole-1-carboxylic acid; D002264:Carboxylic Acids; D007211:Indoles; D010276:Parasympatholytics; D015221:Potassium Channels