Cardioselective Antiischemic ATP-Sensitive Potassium Channel (K_ATP) Openers. 5. Identification of 4-(N-Aryl)-Substituted Benzopyran Derivatives with High Selectivity

Abstract

This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective KATP opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4. showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation KATP opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of KATP openers. Compound 3 is over 20- and 4000-fold more selective for the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the KATP blocker glyburide, indicating that the KATP opening is involved in its mechanism of cardioprotection. With its good oral bioavailability (47%) and plasma elimination half-life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.

KR-31761, a Novel K+ATP-Channel Opener, Exerts Cardioprotective Effects by Opening Both Mitochondrial K+ATP and Sarcolemmal K+ATP Channels in Rat Models of Ischemia/Reperfusion-Induced Heart Injury

“…The cardioprotective effects of KR-31761 appear to be equipotent to those of BMS-180448, as compared with the results from the literature adopting the similar experimental protocols in isolated rat heart (34) and anesthetized ferrets (35), but with a remarkably reduced vasorelaxant activity as shown by a quite smaller potency in relaxing methoxamineprecontracted endothelium-denuded rat aorta (IC 50 values: 23.5 and 1.6 μM for KR-31761 and BMS-180448, respectively). Despite its status as the first cardioselective K + ATP -channel opener to dissociate vasorelaxant activity from cardioprotective activity (14,15,18,19), BMS-180448 was shown to still exert significant vasorelaxant activity in rat aorta contracted with various types of vasoconstrictors (phobol 12,13-dibutyrate, PGF 2α , U46619, KCl, and phenylephrine) via multiple mechanisms (36). Another cardioselective mitoK + ATP -channel opener BMS 191095 was reported to still retain significant vasorelaxant effect on methoxamine-contracted rat aortic preparations with an IC 50 value of 8.96 μM, despite its claimed high cardioselectivity over vasculature (7,16).…”

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.…”

“…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). Clear pharmacological separation between smooth muscle relaxation and cardioprotection has been reported for several K ATP openers such as BMS-180448 and BMS-191095 (Atwal et al, 1993;Grover et al, 1995bGrover et al, , 2001Rovnyak et al, 1997) (chemical structures shown in Fig. 1).…”

Electron-Induced (EI) Mass Fragmentation is Directed by Intra- molecular H-Bonding in Two Isomeric Benzodipyran Systems

“…A resurgence of interest in these compounds since the early 1990s explored their utility across a broad spectrum of activities such as anticancer agents with low toxicity [4], anti-inflammatory agents [5], potassium channel openers with possible cardioprotective properties [6,7], and agonists at serotonergic 5-HT 1A receptors [8].…”