Ryuji Tsuzuki

Novel potassium channel openers. Part 4: transformation of the 1,4-benzoxazine skeleton into 1,4-benzothiazine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroquinoxaline, indoline, and 1,5-benzoxazepine☆

As part of a search for a new potassium channel opener, the 1,4-benzoxazine skeleton derived from the benzopyran skeleton of cromakalim, was transformed into other fused rings such as 1,4-benzothiazine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroquinoxaline, indoline, and 1,5-benzoxazepine. The 1,4-benzothiazine derivative displayed approximately 20 times more potent vasorelaxant activity than cromakalim.

Pharmacologic Profiles of Ym934, a Novel Potassium Channel Opener

Pharmacologic profiles of YM934, a newly synthesized 1,4-benzoxazin derivative K channel opener were evaluated in in vitro and in vivo experiments. In isolated rat portal vein, YM934 and a benzopyran derivative K channel opener lemakalim inhibited the frequency of spontaneous rhythmic contractions concentration de-pendently, with IC50 values of 14 and 38 μM, respectively. These inhibitory effects were competitively antagonized by glibenclamide (an ATP-sensitive K channel blocker; 10-7-3 x 10-6 M). In isolated rabbit aorta, YM934 (10-8-10-6 M) and lemakalim (10-8-l0-6 M) relaxed the contractions induced by 20 mAf KC1 concentration dependency but were ineffective against the contractions induced by 50 mM KC1. YM934 (10_8-3 x KT6 M) and lemakalim (3 x 10-8-10-5 M), but not the calcium antagonist nifedipine, relaxed the contractions induced by norepinephrine (NE 10-6 M) or prostaglandin F2α (PGF2α 3 x 10_6 M) in the aorta. In pentobarbital-anesthetized dogs, YM934 (1–10 μg/kg intravenously, i.v.) dose-dependently increased coronary artery blood flow (CBF), and decreased total peripheral resistance (TPR) and mean blood pressure (MBP). YM934 selectively increased CBF, but had little effect on vertebral, carotid, mesenteric, renal and femoral artery BF. These vasodilatory effects of YM934 were antagonized by glibenclamide. YM934 is a potent K channel opener and possesses potent vasodilatory effects, with particularly pronounced effects on the coronary artery. These effects of YM934 may, like lemakalim, be mediated by opening of ATP-sensitive K channels.

Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ET(A)-selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative (2b). In this paper, we wish to report further details of structure-activity relationships (SARs) of the two regions of the molecule in compound 2b, which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group (6e) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group (6l) or 2-phenylethanesulfonamide group (6q) were well tolerated both in the ET(A) binding affinity and ET(A) selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3mg /kg with a duration of >6.5h. Compound 6e also exhibited a potent antagonistic activity in the pithed rats.