Synthesis and calcium channel antagonist activity of nifedipine analogues containing 4-pyridyl and 3-arylethyloxycarbonyl substituents.
A series of unsymmetrical 3-arylethyl 5-isopropyl ester analogues of nifedipine, in which the 2'-nitrophenyl group at the 4 position is replaced by 2'- or 3'-pyridyl, were prepared and evaluated as calcium channel antagonists. The point of attachment of the pyridyl substituent was a determinant of activity, 2'-pyridyl analogues always being more potent than corresponding 3'-pyridyl analogues. The introduction of a substituent at the para-position of the phenethyl group in 3-phenethyl ester analogues usually enhanced the activity. The most potent compound was 3-(4'-bromophenethyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2'-pyridyl)-3,5-pyridinedicarboxylate. It was 82-fold more potent than nifedipine, and it did not exhibit a negative inotropic effect on guinea pig left atrium. Desirable features in 1,4-dihydropyridine calcium antagonists of the unsymmetrical 3,5-diester type are therefore a 4-(2-pyridyl) substituent in conjunction with a hydrophobic 3-(4-substituted-phenethyl) ester substituent. The arylethyl ester and the 4-(2'-pyridyl) substituents appear to provide important interdependent contributions to the calcium channel antagonist activity.
Akula
M R
MR
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; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives*; D011189:Potassium Chloride / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism
D002121:Calcium Channel Blockers; D011976:Receptors, Muscarinic; D011189:Potassium Chloride; D009543:Nifedipine