Synthesis and calcium channel antagonist activity of nifedipine analogues containing 4(5)-chloro-2-methyl-5(4)-imidazolyl substituent.
Dihydropyridine having substituted imidazole at 4-position in conjunction with various C3, C5 diesters have calcium channel antagonist activity. In this paper a group of dialkyl, dicycloalkyl and diaryl ester analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 replaced by 2-methyl-4(5)-chloro-5(4)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle (GPILSM). The results for the symmetrical ester series showed that increasing the length chain in C3 and C5 ester substituents increased activity. When increasing of the length or lipophilicity accompany with increasing the hindrance, the activity decreased. In asymmetrical diester series, the results showed when R1 is methyl or ethyl, increasing of the lipophilic property in R substituent increases the activity if this high lipophilicity don't accompany with steric hindrance. Our results demonstrate that in symmetrical and asymmetrical series aromatic compounds were more active than aliphatic compounds. In symmetrical diesters compounds, the most active compound was diphenylethyl ester derivative, that it was more active than the reference drug nifedipine. These structure activity data indicate that the 2-methyl-4(5)chloro-5(4)-imidazolyl moiety is bioisoester of 2-nitrophenyl and 2-chlorophenyl moieties.
Davood
A
A
Department of Medicinal Chemistry, Faculty of Pharmacy, Medical Sciences University of Isfahan, Iran.
Khodarahmi
G
G
Alipour
E
E
Dehpour
K
K
Amini
M
M
Shafiee
A
A
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D007093:Imidazoles; D009543:Nifedipine