Substituted aminopyridines as potent and selective phosphodiesterase-4 inhibitors

被引：5

作者：

Côté, B ^{[1
]}

Frenette, R ^{[1
]}

Prescott, S ^{[1
]}

Blouin, M ^{[1
]}

Brideau, C ^{[1
]}

Ducharme, Y ^{[1
]}

Friesen, RW ^{[1
]}

Laliberté, F ^{[1
]}

Masson, P ^{[1
]}

Styhler, A ^{[1
]}

Girard, Y ^{[1
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Pointe Claire, PQ H9R 4P8, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2003年 / 13卷 / 04期

关键词：

D O I：

10.1016/S0960-894X(02)01030-2

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The synthesis and the biological evaluation of new potent phosphodiesterase type 4 (PDE4) inhibitors are presented. This new series was elaborated by replacement of the metabolically resistant phenyl hexafluorocarbinol of L-791,943 (1) by a substituted aminopyridine residue, The structure-activity relationship of N-substitution on 3 led to the identification of (-)-3n which exhibited a good PDE4 inhibitor activity (HWB-TNFalpha=0.12 muM) and an improved pharmacokinetic profile over L-791,943 (rat t(1/2) = 2 h). (-)-3n was well tolerated in ferret with an emetic threshold of 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig (54%, 0.1 mg/kg, ip) as well as the ascaris-induced bronchoconstriction model in sheep (64%/97%. early,,late, 0.5 mg/kg. iv). (C) 2003 Elsevier Science Ltd. All rights reserved.

引用

页码：741 / 744

页数：4

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