Summary— The vasodilating potencies and mechanism of action of a novel pyridinecarboxamidine derivative, KRN4884 (5‐amino‐N‐(2‐(2‐chlorophenyl)ethyl]‐N'‐cyano‐3‐pyridinecarboxamidine] were compared with those of Ki 1769 [N‐cyano‐N'‐(2‐phenylethyl)‐3‐pyridinecarboxamidine] and Ki3005 [N‐[2‐(2‐chlorophenyl)ethyl]‐N'‐cyano‐3‐pyridinecarboxamidine] in rat isolated aortas and in anesthetized normotensive rats. In vitro, KRN4884 (10‐10‐10‐6 M), Ki3005 (10‐10‐10‐6 M) and Ki30O5 (10‐10‐10‐6 M) produced concentration‐dependent relaxations. KRN4884 was about 100‐ and 10‐fold more potent than KU769 and Ki3005, respectively. The relaxant effects of these compounds were antagonized by glibenclamide. In vivo, KRN4884 (1–10 μg/kg, intravenously [iv]), KM769 (10–100 μg/kg, iv) and Ki3005 (3–30 μg/kg, iv) produced dose‐dependent decreases in mean blood pressure with slight increases in heart rate. At 10 μg/kg, iv, the hypotensive effect of KRN4884 was about the same as that of Ki3005 and about 5‐fold more pronounced than that of Ki 1769.The hypotensive action remained for a longer period after KRN4884 administration. In rats pre‐treated with glibenclamide (20 mg/kg, iv), the hypotensive effect of KRN4884 was abolished. These results suggest that the effect of KRN4884 in vitro and in vivo is based on its K channel opening action and that the in vitro vasorelaxant effect of these compounds in aortic rings does not predict their relative hypotensive effect in vivo.

01 Sep 1996·General Pharmacology: The Vascular System

Structure-activity relationship of a novel K+ channel opener, KRN4884, and related compounds in porcine coronary artery

Article

Author: Okada, Yuji ; Izumi, Hideakira ; Izawa, Toshio ; Tanaka, Yoshihiro ; Ogawa, Nobuyuki

1. KRN4884 (5-amino-N-[2-(2-chlorophenyl) ethyl]-N'-cyano-3-pyridinecarboxamidine), Ki3005 (5-deamino KRN4884), Ki5624 (2-dechloro KRN4884) and Ki1769 (5-deamino-2-dechloro KRN4884) produced concentration-dependent relaxations in isolated porcine coronary arteries contracted by 25 mM KC1. The order of relaxant potency was KRN4884 > Ki3005 > Ki5624 > Ki1769. 2. The relaxation induced by these compounds was antagonized by glibenclamide; they had almost no effect on coronary arteries contracted by 60 mM KC1. 3. The present results suggest that these pyridinecarboxamidine derivatives have vasodilating ability based on a K+ channel opening action, and that both the amino groups in the pyridine nucleus and the chlorine atom in the benzene nucleus in pyridinecarboxamidine are important for their potency as a K+ channel opener.

Archives internationales de pharmacodynamie et de therapie

Comparative vasodepressor effects of 3-pyridine derivatives possessing the cyanoamidine or amide structure in pithed rats.

Article

Author: Okada, Y ; Tanaka, Y ; Ogawa, N ; Hasegawa, S ; Nakajima, T ; Kashiwabara, T ; Izawa, T

The potency and mechanism of the vasodepressor action of N-cyano-3-pyridinecarboximidamide and nicotinamide, which are 3-pyridine derivatives possessing cyanoamidine and amide structures, respectively, were studied in pithed rats infused with phenylephrine. The N-substituents of cyanoamidine and amide in the derivatives studied comprised 2-nitroxyethyl (KRN2391 and nicorandil), phenethyl (Ki769 and Ki765) and 2-(2-chlorophenyl)ethyl (Ki3005 and Ki4261) moieties. These derivatives produced vasodepressor actions in a dose-dependent manner, except for Ki4261 which did not show any action below the solubility limit. When the vasodepressor effects of compounds possessing the same N-substituents in cyanoamidine and amide derivatives were compared, the potency of cyanoamidine derivatives was greater than that of amide derivatives, Ki3005 being the most potent. The vasodepressor effects of cyanoamidine and amide derivatives were antagonized by glibenclamide, although the antagonism of the depressor effects of KRN2391 and nicorandil was less pronounced than that of the other derivatives. These results suggest that N-substituents, in addition to the cyanoamidine structure, play an important role in determining the vasodepressor potencies of 3-pyridine derivatives. Furthermore, the vasodepressor effects of these derivatives appear to be based on their K+ channel-opening actions, although those of KRN2391 and nicorandil seem to be partly mediated by a nitrate-like action in addition to their K+ channel-opening action.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Discovery	JP	Kirin Brewery Co. Ltd.	-

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