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.
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.
Carroll
William A
WA
Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Park, IL 60064-6101, USA. william.a.carroll@abbott.com
Altenbach
Robert J
RJ
Bai
Hao
H
Brioni
Jorge D
JD
Brune
Michael E
ME
Buckner
Steven A
SA
Cassidy
Christopher
C
Chen
Yiyuan
Y
Coghlan
Michael J
MJ
Daza
Anthony V
AV
Drizin
Irene
I
Fey
Thomas A
TA
Fitzgerald
Michael
M
Gopalakrishnan
Murali
M
Gregg
Robert J
RJ
Henry
Rodger F
RF
Holladay
Mark W
MW
King
Linda L
LL
Kort
Michael E
ME
Kym
Philip R
PR
Milicic
Ivan
I
Tang
Rui
R
Turner
Sean C
SC
Whiteaker
Kristi L
KL
Yi
Lin
L
Zhang
Henry
H
Sullivan
James P
JP
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
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