Synthesis and calcium channel antagonist activity of alkyl cycloalkyl esters of nifedipine containing pyridinyl substituents.

Drug design and delivery Pub Date : 1989-12-01
M R Akula, W C Matowe, M W Wolowyk, E E Knaus
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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.

含吡啶基取代基硝苯地平烷基环烷基酯的合成及其钙通道拮抗剂活性。
合成硝苯地平(1a)类似物的烷基环烷基酯,其中4位的邻硝基苯基被吡啶基(5-19)取代,并利用毒菌碱受体介导的豚鼠回肠纵向平滑肌Ca(2+)依赖性收缩来评价其作为钙通道拮抗剂。不对称酯(5 ~ 15)的相对活性分布为环戊基>环己基>环丁基,反映了环烷基环尺寸对活性的影响。具有1个r2 -环己基取代基的非对称酯的活性表现为:Me > Et, i-Pr, i-Bu >环己基> t-Bu。C-4吡啶基取代基的附着点也是不对称化合物活性的决定因素(R1 = Me, i-Pr;R2 =环己基,环丁基),相对效价顺序为2-吡啶基> 3-吡啶基> 4-吡啶基。当R1和R2取代基较大时(R1 = R2 =环己基或R1 = i-Pr, R2 =环戊基),反应的相对活性谱为3-吡啶基= 4-吡啶基> 2-吡啶基。因此,C-3和C-5酯取代基似乎对钙通道拮抗剂活性提供了重要的相互作用,从而与1,4-二氢吡啶受体位点相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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