Synthesis and calcium channel antagonist activity of nifedipine analogues containing 1,2-dihydropyridyl in place of the 1,4-dihydropyridyl moiety.
Drug Des Deliv
; 2(3): 177-89, 1988 Feb.
Article
em En
| MEDLINE
| ID: mdl-2855573
ABSTRACT
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).
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Di-Hidropiridinas
/
Bloqueadores dos Canais de Cálcio
/
Nifedipino
/
Canais de Cálcio
/
Contração Muscular
/
Músculo Liso
Limite:
Animals
Idioma:
En
Revista:
Drug Des Deliv
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
1988
Tipo de documento:
Article
País de afiliação:
Canadá