Dihydropyrimidine calcium channel blockers. 4. Basic 3-substituted-4-aryl-1,4-dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive agents

Abstract

We have examined a series of novel dihydropyrimidine calcium channel blockers that contain a basic group attached to either C5 or N3 of the heterocyclic ring. Structure-activity studies show that a 1-(phenylmethyl)-4-piperidinyl carbamate moiety at N3 and sulfur at C2 are optimal for vasorelaxant activity in vitro and impart potent and long-acting antihypertensive activity in vivo. One of these compounds (11) was identified as a lead, and the individual enantiomers 12a (R) and 12b (S) were synthesized. Two key steps of the synthesis were (1) the efficient separation of the diastereomeric ureido derivatives 29a/29b and (2) the high-yield transformation of 2-methoxy intermediates 30a/30b to the (p-methoxybenzyl)thio intermediates 31a/31b. Chirality was demonstrated to be a significant determinant of biological activity, with the dihydropyridine receptor recognizing the enamino ester moiety (12a) but not the carbamate moiety (12b). Dihydropyrimidine 12a is equipotent to nifedipine and amlodipine in vitro. In the spontaneously hypertensive rat, dihydropyrimidine 12a is both more potent and longer acting than nifedipine and compares most favorably with the long-acting dihydropyridine derivative amlodipine. Dihydropyrimidine 12a has the potential advantage of being a single enantiomer.

Synthesis, characterization and biological evaluation of thiazolopyrimidine derivatives

“…[1][2][3] In recent years, interest has also been focused on aza-analogs of 1,4-dihydropyridines such as dihydropyrimidines (DHPMs), which exhibit a pharmacological profile similar to classical dihydropyridine calcium channel modulators. [4][5][6][7][8][9][10] Apart from being well known for their calcium channel blocking activity, the dihydropyrimidines are also being explored for their possible therapeutic effects in treatment of AIDS. 11 This is due to the fact that their particular structure has been found in the natural marine alkaloids batzelladine A and B, which are the first lowmolecular-weight natural products reported in the literature to inhibit the binding of HIV gp-120 to CD4 cells, thus opening up a new area in the development of AIDS therapy.…”

Evaluation of the in vitro antiretroviral potential of some Biginelli-type pyrimidines

“…Aft er nine decades of being ignored, the pharmacological properties of this interesting heterocyclic scaff old attracted worthwhile attention of medicinal chemists (Kappe, 2000). Since the early 1980s, a broad range of biological eff ects, including calcium channel modulation (Rovnyak et al, 1992), adrenoceptor blocking activity (Barrow et al, 2000), antitumor (Klein et al, 2007), antibacterial (Ashok et al, 2007), antioxidant (Stefani et al, 2006) and anti-infl ammatory (Bahekar and Shinde, 2004) activities has been ascribed to this class of heterocycles. DHPMs also possess antiviral activity (Hurst and Hull, 1961).…”

Synthesis and Crystal Structure Analysis of Ethyl-4-(4-acetoxy-phenyl)-3-acetyl-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate

“…More recently dihydropyrimidines (DHPMs) have emerged as the integral backbones of several calcium channel modulators, anti-hypertensive agents. These inherently asymmetric dihydropyrimidine derivatives are not only better calcium channel blockers, but have also been extensively studied to expand the existing SAR (Structure activity relation) and to get further insight into molecular interactions at the receptor level [1][2][3][4] . The present work is a part of our research involving a series of novel dihydropyrimidine derivatives which can be potent mimics of the dihydropyridines.…”