title: 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.
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.
authors.affiliation: Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Park, IL 60064-6101, USA. william.a.carroll@abbott.com
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Altenbach
authors.forename: Hao
authors.initials: H
authors.lastname: Bai
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buckner
authors.forename: Christopher
authors.initials: C
authors.lastname: Cassidy
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coghlan
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Daza
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fey
authors.forename: Michael
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gregg
authors.forename: Rodger F
authors.initials: RF
authors.lastname: Henry
authors.forename: Mark W
authors.initials: MW
authors.lastname: Holladay
authors.forename: Linda L
authors.initials: LL
authors.lastname: King
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.forename: Sean C
authors.initials: SC
authors.lastname: Turner
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Whiteaker
authors.forename: Lin
authors.initials: L
authors.lastname: Yi
authors.forename: Henry
authors.initials: H
authors.lastname: Zhang
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008564:Membrane Potentials; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects
chemical_list: C466801:9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno(3,2-b)quinolin-8(4H)-one 1,1-dioxide; D003499:Cyclic S-Oxides; D015221:Potassium Channels; D015363:Quinolones; D000255:Adenosine Triphosphate