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Synthesis and calcium channel antagonist activity of 3-arylmethyl 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates.

Abstract：

:Unsymmetrical aryl(heteroaryl)methyl isopropyl ester analogues of nifedipine, in which the 2-nitrophenyl group at C-4 is replaced by a 2- or 3-pyridyl substituent, were synthesized and evaluated as calcium-channel antagonists using guinea pig ileal longitudinal smooth muscle. The point of attachment of the C-4 pyridyl substituent was a determinant of activity where the relative potency order was 2-pyridyl greater than 3-pyridyl. Within the C-4 2-pyridyl series of compounds, and electronegative substituent such as a trifluoromethyl or bromo at the 4 position of the benzyl ester substituent or a nitrogen atom at the 1 position of a 4-pyridylmethyl ester substituent, enhanced activity relative to the unsubstituted benzyl ester analogue. In contrast, in the C-4 3-pyridyl class of compounds, a variety of aryl(heteroaryl)methyl ester substituents did not alter potency to any significant extent. A number of compounds in the C-4 2-pyridyl series possessing 4-pyridylmethyl, 4-trifluoromethylbenzyl, 4-bromobenzyl, and 3-pyridylmethyl ester substituents were approximately equipotent to nifedipine. The aryl(heteroaryl)methyl ester and C-4 2-pyridyl substituents therefore appear to provide important interdependent contributions to calcium-channel antagonist activity.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Akula MR,Matowe WC,Wolowyk MW,Knaus EE

doi

10.1023/a:1015941706008

subject

Has Abstract

pub_date

1990-09-01 00:00:00

pages

919-22

issue

9

eissn

0724-8741

issn

1573-904X

journal_volume

7

pub_type

杂志文章

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