title: Dihydropyrimidine calcium channel blockers. 3. 3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents.
abstract: In order to explain the potent antihypertensive activity of the modestly active (IC50 = 3.2 microM) dihydropyrimidine calcium channel blocker 5, we carried out drug metabolism studies in the rat and found 5 is metabolized to compounds 6-10. Two of the metabolites, 6 (IC50 = 16 nM) and 7 (IC50 = 12 nM), were found to be responsible for the antihypertensive activity of compound 5. Potential metabolism of 6 into 7 in vivo precluded our interest in pursuing compounds related to 6. Structure-activity studies aimed at identifying additional aryl-substituted analogues of 7 led to 17g,j,p with comparable potential in vivo, though these compounds were less potent than 7 in vitro. To investigate the effects of absolute stereochemistry on potency, we resolved 7 via diastereomeric ureas 19a,b, prepared from 18 by treatment with (R)-alpha-methylbenzylamine. Our results demonstrate that the active R-(-)-enantiomer 20a of 7 is both more potent and longer acting than nifedipine (1) as an antihypertensive agent in the SHR. The in vivo potency and duration of 20a is comparable to the long-acting dihydropyridine amlodipine. The superior oral antihypertensive activity of 20a compared to that of previously described carbamates 2 (R2 = COOEt) could be explained by its improved oral bioavailability, possibly resulting from increased stability of the urea functionality.
authors.affiliation: Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
authors.forename: K S
authors.initials: KS
authors.lastname: Atwal
authors.forename: B N
authors.initials: BN
authors.lastname: Swanson
authors.forename: S E
authors.initials: SE
authors.lastname: Unger
authors.forename: D M
authors.initials: DM
authors.lastname: Floyd
authors.forename: S
authors.initials: S
authors.lastname: Moreland
authors.forename: A
authors.initials: A
authors.lastname: Hedberg
authors.forename: B C
authors.initials: BC
authors.lastname: O'Reilly
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D008297:Male; D011743:Pyrimidines / Q000138:chemical synthesis*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D011743:Pyrimidines