LONG-ACTING DIHYDROPYRIDINE CALCIUM-ANTAGONISTS .6. STRUCTURE-ACTIVITY-RELATIONSHIPS AROUND 4-(2,3-DICHLOROPHENYL)-3-(ETHOXYCARBONYL)-2-[(2-HYDROXYETHOXY)METHYL]-5-(METHOXYCARBONYL)-6-METHYL-1,4-DIHYDROPYRIDINE

被引:13
作者
ALKER, D
CAMPBELL, SF
CROSS, PE
机构
[1] Pfizer Central Research, Sandwich
关键词
D O I
10.1021/jm00105a004
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The preparation of 4-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-2-[(2-hydroxyethoxy)methyl]-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyridine (2) is described, and its potent calcium antagonist activity on rat aorta (IC50 = 4 x 10(-9) M) and marked tissue selectivity in vitro for vascular smooth muscle over cardiac smooth muscle are established. In order to exploit the excellent in vitro profile of compound 2, a range of analogues were prepared but none were found to have superior calcium antagonist potency and tissue selectivity. Compound 2 has excellent in vivo activity in the anesthetized dog (ED50 = 12-mu-g/kg for reduction of CVR) and a plasma half-life in the conscious dog of 7.2 h. The pharmacokinetic parameters of 2 are compared to those determined for the structurally related compounds amlodipine and felodipine. The plasma clearance for 2 (9.6 mL/min/kg) is similar to that of amlodipine and is consistent with the extended 2-substituent hindering approach to the cytochrome P-450 enzyme responsible for oxidation of the DHP ring to the corresponding pyridine.
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页码:19 / 24
页数:6
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