Synthesis and calcium channel antagonist activity of dialkyl 1,4-dihydro-2,6-dimethyl-4-[4-(1-methoxycarbonyl-1,4-dihydropyridyl)]-3 ,5- pyridinedicarboxylates.
A novel class of dialkyl 1,4-dihydro-2,6-dimethyl-4-[4-(1- methoxycarbonyl-1,4-dihydropyridyl)]-3,5-pyridinedicarboxylates (8-14) were synthesized and evaluated as calcium channel antagonists. The differences in activity among members of this new class of compounds was less than one log unit (IC50 range of 1.12 x 10(-6) to 8.57 x 10(-6) M), relative to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M). The small differences in potency, irrespective of the size of the dialkyl (Me, Et, i-Pr, i-Bu) ester substituents, is attributed to the fact that the N-CO2Me substituent is too far removed from the C-3 and C-5 ester substituents to undergo non-bonded steric interactions. The 4-[4-(1-methoxycarbonyl-1,4-dihydropyridyl) moiety in this new class of compounds is bioisosteric with a C-4 4-nitrophenyl, or a 4-pyridyl, substituent in classical 1,4-dihydropyridines.
Ramesh
M
M
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Matowe
W C
WC
Wolowyk
M W
MW
Knaus
E E
EE
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D004095:Dihydropyridines