F-0401 is a newly synthesized dihydropyridine derivative with both antagonistic activity on platelet-activating factor (PAF) and inhibitory action on thromboxane A2(TXA2) synthetase activity. In the present study, we examined the effects of F-0401 on platelet aggregations in vitro and ex vivo in rabbits. F-0401 prevented PAF-, arachidonic acid (AA)- and collagen-induced platelet aggregations in vitro, but did not prevent the aggregation by ADP. The inhibitory effect of F-0401 on the aggregation by PAF (IC50 value: 3.4 x 10(-6) M) or by the threshold amount of AA (IC50 value: 4.3 x 10(-6) M) had the same potency as that of CV-3988 (a PAF antagonist) and ozagrel a (TXA2 synthetase inhibitor). Ex vivo studies also revealed that the anti-aggregatory effect occurred 1 h after the treatment of F-0401 (> 10 mg/kg, p.o.) and this effect had a tendency to last for 6 h. Nicardipine prevented the platelet aggregation only by PAF (IC50 value: 6.6 x 10(-5) M) in vitro. However, the preventive effect was not seen ex vivo. On the other hand, neither nifedipine nor flunarizine showed any effect on the stimulant-induced platelet aggregation in rabbits. These results suggest that F-0401 has anti-aggregatory action, which is attributable to both PAF antagonistic action and TXA2 synthetase inhibition in vitro and ex vivo.

01 Jan 1993·Folia Pharmacologica Japonica

Pharmacological profile of F-0401, a novel dihydropyridine derivative. (2). The vasodilator action of F-0401 in isolated canine arteries.

Article

Author: Kase, Noriko ; Yamaura, Tetsuaki ; Ohnishi, Haruo

F-0401 ((+/-)-(E)-3-[4-(1-imidazolyl)methylphenyl]-2-propen-1-yl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate) is a newly synthesized dihydropyridine derivative. We investigated the vasodilator action of F-0401 in isolated canine cerebral and peripheral arteries. F-0401 reduced KCl-induced contraction of the arteries in a concentration-dependent manner. The inhibitory action on cerebral arteries was greater than that on the peripheral ones. Its pD'2 values were as follows: Middle cerebral(8.3), basilar(8.1) > coronary(6.9) > femoral, renal, internal carotid, vertebral, mesenteric(6.0-5.5) arteries. The cerebrovascular-selectivity (the ratio of the pD'2 of the basilar artery to that of the femoral one) of F-0401 was 4, 25 and 40 times as large as that of flunarizine, nicardipine and nimodipine, respectively. F-0401 shifted to the right the concentration-response curve for CaCl2 in the depolarized basilar artery (pA2 value: 8.9). However, the reductions of 5-HT and PGF2 alpha-induced contractions by F-0401 in this artery were very weak (pD'2 value:5.9 and < 4.5). These results suggest that F-0401 is a potent cerebrovascular-selective vasodilator and its effects were attributed to the inhibitory effect on the voltage-dependent Ca2+ channels.

01 Jan 1993·Folia Pharmacologica Japonica

Pharmacological profile of F-401, a novel dihydropyridine derivative. (1) Mechanisms of action.

Article

Author: 李文昇 ; 加瀬則子 ; 大西治夫 ; 山浦哲明 ; 田村典彦 ; 高崎和彦 ; 東出康志

F-0401 is a novel dihydropyridine (DHP) derivative with potent vasodilative and anti-aggregatory actions. In the present study, we examined the mechanisms of the actions of F-0401 and obtained the following findings: F-0401 suppressed [3H]nitrendipine binding to rat heart membrane (Ki value: 2.2 x 10(-7) M). CaCl2-induced contractions of rabbit aorta and guinea pig taenia coli were inhibited by F-0401 (pA2 values: 7.7 and 6.6). These results indicated that F-0401 had calcium antagonistic activity slightly less potent than that of the other DHP derivatives. In addition, F-0401 significantly inhibited the activity of thromboxane (TX) A2 synthetase (IC50 value: 2.5 x 10(-7) M) and [3H]PAF binding to rabbit platelets (Ki value: 1.4 x 10(-8) M). The other DHP derivatives tested did not affect TXA2 synthetic activity, and the PAF antagonism of the other derivatives were less than that of F-0401. Neither F-0401 nor the other DHP derivatives inhibited cAMP- or cGMP-dependent phosphodiesterase activity. These results revealed that F-0401 has calcium antagonistic, anti-PAF and TXA2 synthetase inhibitory actions in the same dose ranges.

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Indication	Highest Phase	Country/Location	Organization	Date
Stroke	Preclinical	Japan	UCB Japan Co. Ltd.	-

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