Discovery of L-791,943:: A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor

被引：46

作者：

Guay, D ^{[1
]}

Hamel, P ^{[1
]}

Blouin, M ^{[1
]}

Brideau, C ^{[1
]}

Chan, CC ^{[1
]}

Chauret, N ^{[1
]}

Ducharme, Y ^{[1
]}

Huang, Z ^{[1
]}

Girard, M ^{[1
]}

Jones, TR ^{[1
]}

Laliberté, F ^{[1
]}

Masson, P ^{[1
]}

McAuliffe, M ^{[1
]}

Piechuta, H ^{[1
]}

Silva, J ^{[1
]}

Young, RN ^{[1
]}

Girard, Y ^{[1
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Quebec City, PQ H9R 4P8, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 11期

关键词：

D O I：

10.1016/S0960-894X(02)00190-7

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (1 In) as a potent (HWB TNF-alpha = 0.67 muM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey. (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

页码：1457 / 1461

页数：5

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