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).
Maekawa
T
T
Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Yamamoto
S
S
Igata
Y
Y
Ikeda
S
S
Watanabe
T
T
Shiraishi
M
M
D000284:Administration, Oral; D000818:Animals; D001013:Aorta, Thoracic; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D019806:Cromakalim / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology; D004285:Dogs; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D005996:Nitroglycerin / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists* / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology
C110562:2-(5-bromo-alpha-(tert-butoxyimino)-4-fluoro-2-hydroxybenzyl)-3-hydroxypyridine 1-oxide; D003497:Cyclic N-Oxides; D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; D004110:Diltiazem; D005996:Nitroglycerin