(-)-(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: Ryan M Fryer, Lee C Preusser, Samuel V Calzadilla, Yanhui Hu, Hongyu Xu, Kennan C Marsh, Bryan F Cox, C Thomas Lin, Murali Gopalakrishnan, Glenn A Reinhart
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 44 Issue 2 Pg. 137-47 (Aug 2004) ISSN: 0160-2446 [Print] United States
• PMID: 15243293 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno(3,2-b)quinolin-8(4H)-one 1,1-dioxide
• Amides
• Benzophenones
• Cyclic S-Oxides
• Cyclobutanes
• Nitriles
• Pharmaceutical Vehicles
• Potassium Channels
• Quinolones
• WAY 133537
• Zeneca ZD 6169
• Polyethylene Glycols
• Adenosine Triphosphate
• Nifedipine

Topics

• Adenosine Triphosphate (chemistry)
• Amides (blood, pharmacology)
• Animals
• Benzophenones (blood, pharmacology)
• Blood Pressure (drug effects)
• Cyclic S-Oxides (blood, pharmacology)
• Cyclobutanes (blood, pharmacology)
• Disease Models, Animal
• Dogs
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Electrocardiography (methods)
• Heart Rate (drug effects)
• Hypotension (chemically induced)
• Infusions, Intravenous
• Ion Channel Gating (drug effects, physiology)
• Male
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects)
• Nifedipine (blood, pharmacology)
• Nitriles (blood, pharmacology)
• Pharmaceutical Vehicles (administration & dosage, chemistry)
• Polyethylene Glycols (administration & dosage, chemistry)
• Potassium Channels (drug effects, physiology)
• Quinolones (blood, pharmacology)
• Tachycardia (chemically induced)
• Urinary Bladder (drug effects, physiology)
• Urinary Incontinence (drug therapy, physiopathology)
• Vascular Resistance (drug effects)