US EPA

7431110 

Journal Article 

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

Rovnyak, GC; Atwal, KS; Hedberg, A; Kimball, SD; Moreland, S; Gougoutas, JZ; O'Reilly, BC; Schwartz, J; Malley, MF; , 

1992 

Yes 

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 

AMER CHEMICAL SOC 

WASHINGTON 

35 

17 

3254-3263 

English 

1387168 

10.1021/jm00095a023 

WOS:A1992JK32400023 

https://pubs.acs.org/doi/abs/10.1021/jm00095a023
Exit
 

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. 

3,6 dihydro 4 methyl 2 thioxo 6 (2 trifluoromethylphenyl) 1,5 pyrimidinedicarboxylic acid 1 [1 (4 fluorobenzyl) 4 piperidyl] 5 isopropyl ester; alkyl group; amlodipine; antihypertensive agent; calcium channel blocking agent; carbamic acid; dihydropyrimidine derivative; drug receptor; ester; nifedipine; pyrimidine derivative; unclassified drug; alkylation; animal model; antihypertensive activity; article; drug efficacy; drug potency; drug structure; drug synthesis; enantiomer; hypertension; nonhuman; oral drug administration; priority journal; rat; spontaneously hypertensive rat; structure activity relation; vasodilatation