title: Dihydropyrimidine calcium channel blockers. 2. 3-substituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.
abstract: To enhance the intrinsic potency of dihydropyrimidine calcium channel blockers, we have modified the structure of previously described 2-heteroalkyl-1,4-dihydropyrimidines 2 to 3-substituted 1,4-dihydropyrimidines 3. Structure-activity studies using potassium-depolarized rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more potent than either ortho- or meta-monosubstituted compounds. While vasorelaxant activity was critically dependent on the size of the C5 ester group, isopropyl ester being the best, a variety of substituents (carbamate, acyl, sulfonyl, alkyl) were tolerated at N3. Our results show dihydropyrimidines 3 are significantly more potent than corresponding 2-heteroalkyl-1,4-dihydropyrimidines 2 and only slightly less potent than similarly substituted 2-heteroalkyl-1,4-dihydropyridines 4 and 5. Whereas dihydropyridine enantiomers usually show 10-15-fold difference in activity, the enantiomers of dihydropyrimidine 3j show more than a 1000-fold difference in activity. These results strengthen the requirement of an enamino ester for binding to the dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.
authors.affiliation: Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
authors.forename: K S
authors.initials: KS
authors.lastname: Atwal
authors.forename: G C
authors.initials: GC
authors.lastname: Rovnyak
authors.forename: S D
authors.initials: SD
authors.lastname: Kimball
authors.forename: D M
authors.initials: DM
authors.lastname: Floyd
authors.forename: S
authors.initials: S
authors.lastname: Moreland
authors.forename: B N
authors.initials: BN
authors.lastname: Swanson
authors.forename: J Z
authors.initials: JZ
authors.lastname: Gougoutas
authors.forename: J
authors.initials: J
authors.lastname: Schwartz
authors.forename: K M
authors.initials: KM
authors.lastname: Smillie
authors.forename: M F
authors.initials: MF
authors.lastname: Malley
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D011743:Pyrimidines