Synthesis and Biological Activity of Novel 2-(α-Alkoxyimino)benzylpyridine Derivatives as K⁺ Channel Openers

Abstract

The search for novel K⁺ channel openers with a non-benzopyran skeleton, unlike cromakalim, led to the discovery of a new series of (Z)-2-(α-alkoxyimino)benzylpyridine derivatives. Synthesis was achieved by using a (Z)-dominant condensation reaction of benzoylpyridines with O-alkylhydroxylamines, followed by m-chloroperbenzoic acid (m-CPBA) oxidation. The compounds were tested for thier vasorelaxant activity in tetraethylammonium chloride (TEA) and BaCl₂- and high KCl-induced contration of rat aorta to identify potential K⁺ channel openers, and also for their effects of the coronary blood flow (CBF) after intracoronary injection in anesthetized dogs. A large number of the 2-(α-alkoxyimino)benzylpyridines strongly inhibited TEA and BaCl₂-induced contraction, had no effect on 80 mM KCl-induced contraction, and increased the CBF to more than 200% of the basal flow at 10-30 μg/dog. In particular, (Z)-2-[5-bromo-α-(tert-butoxyimino)-4-fluoro-2-hydroxybenzyl]-3-hydroxypyridine 1-oxide (7d) showed highly potent vasorelaxant activity (EC₅₀=0.28 μM) comparable to that of levcromakalim (EC₅₀=0.17 μM), and gave a significantly longer-lasting increase (T_1/2=30 min) in the CBF compared to levromakalim, nicorandil, nitroglycerin, or diltiazem (T_1/2=5.2, 0.9, 0.4, and 2.2 min, respectively). It also exhibited a stable and long-lasting hypotensive effect (over 7 h) upon oral administration of 1 mg/kg in spontaneously hypertensive rats (SHRs).