Synthesis and biological activity of novel 2-(alpha-alkoxyimino)benzylpyridine derivatives as K+ channel openers

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-(alpha-alkoxyimino)benzylpryridine 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 their vasorelaxant activity in tetraethylammonium chloride (TEA) and BaCl2- and high KCl-induced contraction of rat aorta to identify potential K+ channel openers, and also for their effects on the coronary blood flow (CBF) after intracoronary injection in anesthetized dogs. A large number of the 2-(alpha-alkoxyimino)benzylpyridines strongly inhibited TEA and BaCl2-induced contraction, had no effect on 80 nM KCl-induced contraction, and increased the CBF to more than 200% of the basal flow at 10-30 micrograms/dog. In particular, (Z)-2-[5-bromo-alpha-(tert-butoxyimino)-4-fluoro-2-hydroxybenzyl]- 3- hydroxypyridine 1-oxide (7d) showed highly potent vasorelaxant activity (EC50 = 0.28 microM) comparable to that of levcromakalim (EC50 = 0.17 microM), and gave a significantly longer-lasting increase (T1/2 = 30 min) in the CBF compared to levcromakalim, nicorandil, nitroglycerin, or diltiazem (T1/2 = 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).