Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1,2-dihydropyridyl in place of the 1,4-dihydropyridyl moiety.
Calcium channel antagonist activities of the 1,2-dihydropyridines (9) were determined using the muscarinic-receptor mediated Ca2+ dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative potency order for 4-substituted analogs 9 was phenyl greater than 3-trifluoromethyl(nitro)phenyl greater than 4- and 2-trifluoromethyl(nitro)phenyl. Increasing the size of the alkyl ester substituents (9h) enhanced activity. The test results indicate that the 1,2-dihydropyridyl ring system (9) is partially bioisosteric with the 1,4-dihydropyridyl ring system (10). Competitive [3H]-nitrendipine binding studies indicated that the affinities of the 1,2-dihydropyridine analogues were much lower than expected from their ID50 activities, suggesting that these analogues inhibit calcium channels by a different receptor mechanism. In the synthetic work, Hantzsch condensation of aldehydes (3) with alkyl acetoacetates (4) afforded 3,5-dialkyl 2,6-dimethyl-4-(substituted-phenyl)-1,4-dihydropyridine-3,5-dicarboxylat es (5). Oxidation of 5 gave the aromatic pyridines (6) which were elaborated to the l-methylpyridinium methyl sulphates (7) and then to the perchlorates (8). Sodium borohydride reduction of 8 in aqueous ethanol gave 3,5-dialkyl 1,2,6-trimethyl-4-(substituted-phenyl)-1,2-dihydropyridine-3, 5-dicarboxylates (9).
Soboleski
D A
DA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Li-Kwong-Ken
M C
MC
Wynn
H
H
Triggle
C R
CR
Wolowyk
M W
MW
Knaus
E E
EE
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D004095:Dihydropyridines; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007421:Intestine, Small / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D009568:Nitrendipine / Q000378:metabolism; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D007202:Indicators and Reagents; D009568:Nitrendipine; D009543:Nifedipine