(-)-(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

Journal of Cardiovascular Pharmacology
Ryan M FryerGlenn A Reinhart

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 incr...Continue Reading

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Citations

Jun 14, 2005·Current Opinion in Chemical Biology·Glenn A ReinhartGary A Gintant
Jan 6, 2007·Cell Death and Differentiation·H ZhangC Tse
Jun 29, 2006·Neurourology and Urodynamics·Ehab ElzayatJacques Corcos
Jan 9, 2014·The Journal of Pharmacology and Experimental Therapeutics·Ryan M FryerLouise K Modis
Nov 6, 2007·American Journal of Physiology. Heart and Circulatory Physiology·Patricia N BanforRyan M Fryer
Sep 16, 2005·Journal of Medicinal Chemistry·Philip R KymChristine A Collins

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