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Synthesis and Calcium Channel Antagonist Activity of Dialkyl 1,4‐Dihydro‐2,6‐dimethyl‐4‐[4‐(1‐methoxycarbonyl‐1,4‐dihydropyridyl)]‐3,5‐ pyridinedicarboxylates
Author(s) -
Ramesh Manian,
Matowe Wandikayi C.,
Wolowyk Michael W.,
Knaus Edward E.
Publication year - 1999
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(199911)332:11<385::aid-ardp385>3.0.co;2-9
Subject(s) - chemistry , substituent , moiety , steric effects , stereochemistry , calcium channel , nifedipine , antagonist , potency , calcium , in vitro , organic chemistry , receptor , biochemistry
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 (IC 50 range of 1.12 × 10 ‐6 to 8.57 × 10 ‐6 M), relative to the reference drug nifedipine (IC 50 = 1.43 × 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‐CO 2 Me 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.