Cardioselective anti-ischemic ATP-sensitive potassium channel openers

Abstract

The ATP-sensitive potassium channel (Katp) openers cromakalim (1), pinacidil (2), aprikalim (3), and diazoxide (4) are potent antihypertensive agents acting via peripheral H Diazoxide (4) vasodilation.1 The original excitement about the discovery

Pharmacologic Profile of the Selective Mitochondrial‐KATP Opener BMS‐191095 for Treatment of Acute Myocardial Ischemia

“…Early work from our laboratories clearly established a complete lack of correlation between vasorelaxant activity, action potential shortening, and cardioprotective activity (2,13,28). This was fortunate because it suggested the possibility of developing selective cardioprotective K ATP openers, but was unfortunate because the only screen available for structure-activity determinations (SAR) was ischemia itself.…”

In Vivo Characterization of the Mitochondrial Selective KATPOpener (3R)-trans-4-((4-Chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril Monohydrochloride (BMS-191095): Cardioprotective, Hemodynamic, and Electrophysiological Effects

“…The cardioprotective effects K ATP openers are abolished by glyburide and 5-HD. Although the broad class of K ATP openers exert cardioprotective effects, there is some diversity in terms of the pharmacological profiles of K ATP openers with some being potent vasodilators, some having effects on pancreatic ␤-cells, and others having no effect on cardiac action po- BCL 400 ms 0.0 (Atwal et al, 1993;Inagaki et al, 1996;Rovnyak et al, 1997). Studies from several laboratories showed a poor correlation between action potential shortening and cardioprotection for compounds and preconditioning, suggesting that sarcolemmal activation may not be important (Yao and Gross, 1994;Grover et al, 1995b;Grover and Sleph, 1995;Hamada et al, 1998).…”

“…Studies from several laboratories showed a poor correlation between action potential shortening and cardioprotection for compounds and preconditioning, suggesting that sarcolemmal activation may not be important (Yao and Gross, 1994;Grover et al, 1995b;Grover and Sleph, 1995;Hamada et al, 1998). Structureactivity studies using benzopyran and cyanoguanidine analogs showed a clear delineation between vasodilator and APD shortening effects versus cardioprotection (Atwal et al, 1993;Rovnyak et al, 1997). Despite this unusual profile, the cardioprotective effects of these selective agents were completely abolished by K ATP blockers.…”

“…Numerous K ATP subtypes exist and seem to be differentially expressed in various tissues (Inoue et al, 1991;Atwal et al, 1993;Grover et al, 1995a;Chutkow et al, 1996;Inagaki et al, 1996). Pharmacological data suggest that mitochondrial K ATP activation is critical for cardioprotection and that this channel is distinct from sarcolemmal channels (Garlid et al, 1996(Garlid et al, , 1997Liu et al, 1998;Nakai et al, 2001).…”

Synthesis, Characterization, and Antihypertensive Evaluation of Some Novel 2,2,8,8-Tetramethyl-2,3,7,8-tetrahydro-4,6-diamino-3,7-dihydroxy-6,7-epoxy-benzo-[1,2-b:5,4-b′]dipyran Derivatives

“…Potassium channel classifications and their pharmacological activities have been reviewed extensively [3]. The term "potassium channel openers (KCOs)" was introduced to designate a group of novel synthetic molecules which are specified by cromakalim.…”