Discovery and structure-activity relationships of a novel series of benzopyran-based K(ATP) openers for urge urinary incontinence.
A novel series of benzopyran derivatives were synthesized and evaluated as K(ATP) channel openers. Structure-activity relationships were investigated around 4-position of the benzopyran nucleus. Optimization of 4-substituent with some heterocyclic rings led to compound 13b bearing a benzo[d]isoxazol-3-one moiety as a potent and selective K(ATP) channel opener in vitro. In two anesthetized rat models of myogenic bladder overactivity, compound 13b was found to inhibit spontaneous bladder contractions.
Zhang
Xuqing
X
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19341, USA. xzhang5@prdus.jnj.com
Qiu
Yuhong
Y
Li
Xiaojie
X
Bhattacharjee
Sheela
S
Woods
Morgan
M
Kraft
Patricia
P
Lundeen
Scott G
SG
Sui
Zhihua
Z
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D004195:Disease Models, Animal; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists*; D051381:Rats; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects / Q000503:physiopathology; D053202:Urinary Incontinence, Urge / Q000188:drug therapy*
D001578:Benzopyrans; D024661:Potassium Channels, Inwardly Rectifying