Synthesis and calcium channel antagonist activity of alkyl cycloalkyl esters of nifedipine containing pyridinyl substituents.
Drug Des Deliv
; 5(2): 117-23, 1989 Dec.
Article
em En
| MEDLINE
| ID: mdl-2577981
ABSTRACT
Alkyl cycloalkyl esters of nifedipine (1a) analogues, in which the ortho-nitrophenyl group at position 4 is replaced by pyridinyl (5-19) were synthesized and evaluated as calcium channel antagonists using the muscarinic receptor-mediated Ca(2+)-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative activity profile for unsymmetrical esters (5-15), which indicated the effect of cycloalkyl ring size on activity, was cyclopentyl > cyclohexyl > cyclobutyl. In addition unsymmetrical esters, possessing one R2-cyclohexyl substituent, exhibited an activity profile dependent upon the nature of the R1-alkyl ester substituent with Me > Et, i-Pr, i-Bu > cyclohexyl > t-Bu. The point of attachment of the C-4 pyridinyl substituent was also a determinant of activity for unsymmetrical compounds (R1 = Me, i-Pr; R2 = cyclohexyl, cyclobutyl) where the relative potency order was 2-pyridinyl > 3-pyridinyl > 4-pyridinyl. In contrast, when the R1 and R2-substituents are larger in size (R1 = R2 = cyclohexyl or R1 = i-Pr, R2 = cyclopentyl) the relative activity profile was 3-pyridinyl = 4-pyridinyl > 2-pyridinyl. The C-3 and C-5 ester substituents therefore appear to provide important interdependent contributions to calcium channel antagonist activity, and hence to interaction with the 1,4-dihydropyridine receptor site.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Bloqueadores dos Canais de Cálcio
/
Nifedipino
Limite:
Animals
Idioma:
En
Revista:
Drug Des Deliv
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
1989
Tipo de documento:
Article
País de afiliação:
Canadá