6-Substituted 2,2-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openers.
In the course of our study to find an ideal antihypertensive potassium channel opener (KCO), N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-ben zopyran-4-carboxamide (13f, KC-515) showed a highly potent, slow and long-lasting antihypertensive effect with reduced reflex tachycardia, together with the beneficial effects of KCO such as improvement in lipid metabolism. These profiles identify KC-515 as a potential candidate. In conscious spontaneously hypertensive rats (SHR), the onset of the hypotensive effect of KC-515 (13f) was gradual and the maximum response was attained at around 6 h after dosing. The duration of action was over 18 h for 0.1 mg/kg. When administered to Zucker rats for 2 weeks with 0.03-0.3 mg/kg po range in the antihypertensive doses in hypertensive rat models, KC-515 (13f) significantly and dose-dependently reduced serum triglycerides to less than 70% of control without affecting total cholesterol.
Taka
N
N
Fuji-gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. takanok@chugai.pharm.co.jp
Koga
H
H
Sato
H
H
Ishizawa
T
T
Takahashi
T
T
Imagawa
J
J
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015221:Potassium Channels / Q000819:agonists*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D005466:Fluorocarbons
D000959:Antihypertensive Agents; D001578:Benzopyrans; D000960:Hypolipidemic Agents; D015221:Potassium Channels; C416380:KC 515; D005466:Fluorocarbons