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Synthesis and Structure-Activity Relationships of a Novel Series of 2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide K(ATP) Channel Openers: Discovery of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9- hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a Potent K(ATP) Opener That Selectively Inhibits Spontaneous Bladder Contractions

Synthesis and Structure-Activity Relationships of a Novel Series of 2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide K(ATP) Channel Openers: Discovery of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9- hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a Potent K(ATP) Opener That Selectively Inhibits Spontaneous Bladder Contractions

William A Carroll, Robert J Altenbach, Hao Bai, Jorge D Brioni, Michael E Brune, Steven A Buckner, Christopher Cassidy, Yiyuan Chen, Michael J Coghlan, Anthony V Daza, Irene Drizin, Thomas A Fey, Michael Fitzgerald, etc.

J Med Chem. 2004 Jun 3;47(12):3163-79.

PMID: 15163196

Abstract:

Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K(ATP) openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP227609667	A-278637		227609-66-7	Price

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