Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1-oxido-2-pyridyl in place of the 2-nitrophenyl moiety.
Analogues (5) of nifedipine (1a), in which the 2-nitrophenyl at position 4 is replaced by 1-oxido-2-pyridyl, were synthesized and evaluated as calcium channel antagonists using the muscarinic receptor-mediated Ca2+-dependent contraction of guinea pig ileal longitudinal smooth muscle. The replacement resulted in a significant loss of activity. In the case of the symmetrical dialkyl esters (5a-e), activity was enhanced by increasing the size of the alkyl ester substituents, the relative order of potency being i-Bu congruent to t-Bu greater than i-Pr greater than Et and Me. Our results show that the 1-oxido-2-pyridyl substituent is not a useful isostere of the 2-nitrophenyl moiety of nifedipine. In the synthetic work, Hantzsch condensation of 2-pyridinecarboxaldehyde 1-oxide (4) with equimolar quantities of alkyl acetoacetates (2) and alkyl 3-aminocrotonates (3) afforded dialkyl 1,4-dihydro-2,6-dimethyl-4-(1-oxido-2-pyridyl)-3,5-pyridinedicarboxylate s (5).
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* / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D002217:Carbachol; D009543:Nifedipine