title: (-)-(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: hemodynamic comparison to ZD-6169, WAY-133537, and nifedipine in the anesthetized canine.
abstract: The therapeutic utility of KATP channel opening agents (KCOs) in the treatment of overactive bladder may be limited by hypotension as a result of insufficient selectivity in vivo for bladder versus vasculature smooth muscle. Recently, we demonstrated that the putative uroselective KCOs, A-278637, ZD-6169, and WAY-133537 suppress unstable bladder contraction in an in vivo pre-clinical pig model of detrusor instability secondary to partial outlet obstruction. In the present study in the anesthetized dog we targeted plasma concentrations 3-, 10-, and 30-fold above a common index of in vivo efficacy (EC35) for suppression of unstable bladder contraction in pigs, to provide a comprehensive cardiovascular profile of these compounds. When compared at similar multiples of efficacy, dose-dependent reductions in SVR were greater in ZD-6169 and WAY-133537-treated animals versus A-278637. A-278637, unlike ZD-6169 or WAY-133537, produced no effect on MAP at concentrations 10-fold above the EC35. At concentrations 30-fold above the EC35, MAP in A-278637-treated animals was reduced -11% from baseline versus -24% and -42% for ZD-6169 and WAY-133537. Accordingly, at plasma concentrations approximately 30-fold above the EC35 reflex-mediated increases in HR were modest for A-278637-treated animals (15% above baseline) versus ZD-6169 (22%) or WAY-133537 (35%). Increases in both dP/dt and cardiac output occurred at lower therapeutic multiples and were greater in magnitude for animals treated with WAY-133537 (66% and 64% above baseline, respectively, 60 minutes into compound infusion) and ZD-6169 (10% and 13%) versus A-278637 (-2% and 6%). Thus, A-278637 exerted lesser effects on cardiovascular function at equivalent multiples of the EC35 than either ZD-6169 or WAY-133537. These data suggest that A-278637 possesses a greater functional selectivity for urinary bladder versus vascular smooth muscle in vivo and that A-278637 may exhibit a more favorable therapeutic index than either ZD-6169 or WAY-133537.
authors.affiliation: Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6119, USA. fryer@abbott.com
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Lee C
authors.initials: LC
authors.lastname: Preusser
authors.forename: Samuel V
authors.initials: SV
authors.lastname: Calzadilla
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Xu
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: C Thomas
authors.initials: CT
authors.lastname: Lin
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000577:Amides / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001577:Benzophenones / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000097:blood / Q000494:pharmacology*; D003503:Cyclobutanes / Q000097:blood / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography / Q000379:methods; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009543:Nifedipine / Q000097:blood / Q000494:pharmacology*; D009570:Nitriles / Q000097:blood / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D015363:Quinolones / Q000097:blood / Q000494:pharmacology*; D013610:Tachycardia / Q000139:chemically induced; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D014549:Urinary Incontinence / Q000188:drug therapy / Q000503:physiopathology; D014655:Vascular Resistance / 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; D000577:Amides; D001577:Benzophenones; D003499:Cyclic S-Oxides; D003503:Cyclobutanes; D009570:Nitriles; D014677:Pharmaceutical Vehicles; D015221:Potassium Channels; D015363:Quinolones; C119323:WAY 133537; C095007:Zeneca ZD 6169; D011092:Polyethylene Glycols; D000255:Adenosine Triphosphate; D009543:Nifedipine