dihydropyridines and dazoxiben

An approach to the design of potential combined antithrombotic-antihypertensive agents is described. A series of 1,4-dihydropyridines bearing a 1H-imidazol-1-yl or pyrid-3-yl substituted side chain in the 2-position were synthesized and tested for antihypertensive activity in spontaneously hypertensive rats and for inhibition of TXA2 synthetase in rabbit platelets, in vitro. 1,4-Dihydro-2-(1H-imidazol-1-ylmethyl)-6-methyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester (1) was shown to be similar in potency to nitrendipine as an antihypertensive agent. Compound 1 inhibited TXA2 synthetase in rabbit and human platelets in vitro and reduced plasma TXB2 levels in rats at antihypertensive dose levels. The reductions in thromboxane production observed in vivo and in vitro were accompanied by enhanced levels of 6-KPGF1 alpha, reflecting diversion of the arachidonic acid cascade toward prostacyclin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Chemical Phenomena; Chemistry; Dihydropyridines; Drug Design; Fibrinolytic Agents; Humans; Hypertension; Imidazoles; Nitrendipine; Rats; Rats, Inbred SHR; Structure-Activity Relationship; Thromboxane B2; Thromboxane-A Synthase

Wy 27569 (1,4 dihydro-2-[imidazol-1-yl-methyl]-6-methyl-4- [3-nitrophenyl] pyridine-3,5, dicarboxylic acid 3-ethyl 5-methyl diester) is a combined calcium channel blocker and thromboxane synthetase inhibitor. This article reports the in vivo and in vitro pharmacological studies demonstrating these properties. Wy 27569 evoked rightward shifts and depressed the maximum of calcium dose response curves in potassium depolarised rat aortas [concentration required to inhibit the response by 50% (IC50) = 7.3 nM]. The calcium channel blocker nitrendipine exhibited a similar profile to, although more potent than, Wy 27569 (IC50 = 0.28 nM). Comparison of the data obtained in aortas with the effects of these compounds in electrically stimulated isolated ventricle strips (IC50 for Wy 27569 = 8.3 microM, IC50 for nitrendipine = 0.41 microM) suggests that Wy 27569, like nitrendipine, is a vascular selective calcium channel blocker. Wy 27569 and the thromboxane synthetase inhibitor dazoxiben inhibited the collagen-stimulated production of thromboxane B2 (TXB2, IC50 = 3.9 and 2.8 microM, respectively) and, over the same concentration range, enhanced the production of immunoreactive 6 keto prostaglandin F1 alpha (6 keto-PGF1 alpha) by human platelet rich plasma. Single doses of Wy 27569 (0.3-10 mg kg-1 p.o.) or dazoxiben (3-10 mg kg-1 p.o.) evoked a dose-related reduction of TXB2 and enhancement of immunoreactive 6 keto PGF1 alpha levels in rat plasma and serum. Nitrendipine (0.3-10 mg kg-1 p.o.) had no significant effect on either eicosanoid.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Female; Humans; Imidazoles; In Vitro Techniques; Male; Nitrendipine; Prostaglandins F; Rats; Rats, Inbred SHR; Thromboxane B2; Thromboxane-A Synthase