(-)-(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 novel ATP-sensitive potassium channel opener efficacious in suppressing urinary bladder contractions. II. in vivo characterization.
ATP-sensitive potassium (K(ATP)) channel openers (KCOs) have been shown to inhibit spontaneous myogenic contractile activity of the urinary bladder, a mechanism hypothesized to underlie detrusor instability and symptoms of overactive bladder. However, the therapeutic utility of KCOs has been limited by a lack of differentiation of bladder versus vascular effects. In this study, we evaluated the in vivo potency and bladder selectivity 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 novel dihydropyridine KCO, in a pig model of detrusor instability secondary to partial bladder outlet obstruction. For comparison, we profiled two KCOs, ((R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (WAY-133537) and (S)-N-(4-benzoylphenyl)-3,3,3-trifluro-2-hydroxy-2-methyl-propionamide (ZD6169), reported previously to have improved bladder selectivity in vivo and a calcium channel blocker, nifedipine. Effective doses of A-278637, WAY-133537, ZD6169, and nifedipine to inhibit unstable contraction area under the curve by 35% and to decrease mean arterial pressure by 10% were 4.2 and 12, 109 and 51, 661 and 371, and 136 and 30 nmol/kg i.v., yielding corresponding bladder selectivity ratios of 3, 0.5, 0.6, and 0.2. Therefore, A-278637 was approximately 5- to 6-fold more bladder-selective than the other KCOs and 15-fold more selective than nifedipine, the latter approximately 4.5-fold vascular-selective. The potency of KCOs to inhibit unstable contraction in vivo was accurately predicted by their potency to inhibit spontaneous contractile activity of pig detrusor strips in vitro. These results indicate that A-278637, with enhanced potency and bladder selectivity compared with the other compounds evaluated, could serve as a useful tool in the investigation of smooth muscle K(ATP) channel openers as novel therapeutic agents for the treatment of overactive bladder.
Brune
Michael E
ME
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Illinois 60064, USA. michael.e.brune@abbott.com
Fey
Thomas A
TA
Brioni
Jorge D
JD
Sullivan
James P
JP
Williams
Michael
M
Carroll
William A
WA
Coghlan
Michael J
MJ
Gopalakrishnan
Murali
M
D018528:ATP-Binding Cassette Transporters; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D003503:Cyclobutanes / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D054086:KATP Channels; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D015363:Quinolones / Q000494:pharmacology*; D013552:Swine; D001743:Urinary Bladder / Q000502:physiology*
C466801:9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno(3,2-b)quinolin-8(4H)-one 1,1-dioxide; D018528:ATP-Binding Cassette Transporters; D000577:Amides; D001577:Benzophenones; D003499:Cyclic S-Oxides; D003503:Cyclobutanes; D054086:KATP Channels; D009570:Nitriles; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D015363:Quinolones; C119323:WAY 133537; C095007:Zeneca ZD 6169; C092520:uK-ATP-1 potassium channel; D009543:Nifedipine