Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.
2-Heterosubstituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecar box ylic acid esters 8, which lack the potential CS symmetry of dihydropyridine calcium channel blockers, were prepared and evaluated for biological activity. Biological assays using potassium-depolarized rabbit aorta and radioligand binding techniques showed that some of these compounds are potent mimics of dihydropyridine calcium channel blockers. The combination of a branched ester (e.g. isopropyl, sec-butyl) and an alkylthio group (e.g. SMe) was found to be optimal for biological activity. When compared directly with similarly substituted 2-heteroalkyldihydropyridines 9, dihydropyrimidines 8 were found to be 30-fold less active. The solid-state structure of dihydropyrimidine analogue 8g shows that these compounds can adopt a molecular conformation which is similar to the reported conformation of dihydropyridine calcium channel blockers.
Atwal
K S
KS
Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Rovnyak
G C
GC
Schwartz
J
J
Moreland
S
S
Hedberg
A
A
Gougoutas
J Z
JZ
Malley
M F
MF
Floyd
D M
DM
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000494:pharmacology; D006168:Guinea Pigs; D008968:Molecular Conformation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009568:Nitrendipine / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D011743:Pyrimidines; D009568:Nitrendipine