Cardiovascular Profile of a Novel Potassium Channel Opener, KRN4884

Abstract

ZNTRODUCTZONATP-sensitive K+-channel (KAT,,) openers are a new class of vasodilators comprising seven groups with different moieties, as described by Edwards and Weston (5). Those with a pyridine moiety, such as nicorandil and KRN2391, are not specific K+-channel openers because they also show a nitrate-like action due to their nitrate moiety (21,29). In contrast, nicorandil derivatives and KRN239 1 derivatives, which do not possess a nitrate moiety, showed K+-channel opening action without the nitrate-like action (8,31). KRN239 1 derivatives were more potent than nicroandil derivatives possessing corresponding N-substituents (8,31). KRN4884 had the most potent vasodilator action among K+-channel openers with a pyridine moiety (10). In the present review, we outline the nonclinical pharmacological profile of KRN4884. (Fig. la) was converted to imidate (Fig. Ib) by acid-promoted reaction with l-propanol, followed by alkalinization. Imidate was then transformed to cyanoimidate (Fig. lc) by treatment with cyanamide in aqueous phosphate buffer solution. The reaction of cyanoimidate with 2-(2-chlorophenyI)ethylamine in methanol gave KRN4884. PRECLINICAL PHARMACOLOGY Antihypertensive Effects in RatsThe hypotensive effects of KRN4884 by oral (p.0.) administration were examined in normotensive Wistar-Kyoto rats (WKYs), spontaneously hypertensive rats (SHRs) (14),