Discovery of MK-0952, a selective PDE4 inhibitor for the treatment of long-term memory loss and mild cognitive impairment

被引：37

作者：

Gallant, Michel ^{[1
]}

Aspiotis, Renee ^{[1
]}

Day, Stephen ^{[1
]}

Dias, Rebecca ^{[2
]}

Dube, Daniel ^{[1
]}

Dube, Laurence ^{[1
]}

Friesen, Richard W. ^{[1
]}

Girard, Mario ^{[1
]}

Guay, Daniel ^{[1
]}

Hamel, Pierre ^{[1
]}

Huang, Zheng ^{[1
]}

Lacombe, Patrick ^{[1
]}

Laliberte, Sebastien ^{[1
]}

Levesque, Jean-Francois ^{[1
]}

Liu, Susana ^{[1
]}

Macdonald, Dwight ^{[1
]}

Mancini, Joseph ^{[1
]}

Nicholson, Donald W. ^{[1
]}

Styhler, Angela ^{[1
]}

Townson, Karen ^{[2
]}

Waters, Kerry ^{[2
]}

Young, Robert N. ^{[1
]}

Girard, Yves ^{[1
]}

机构：

[1] Merck Frosst Ctr Therapeut Res, Kirkland, PQ H9H 3L1, Canada

[2] Neurosci Res Ctr, Dept Vivo Neurosci, Harlow CM20 2QR, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 22期

关键词：

MK-0952; PDE4; inhibitors; Mild cognitive impairment; TASTE-AVERSION; OBJECT MEMORY; IN-VITRO; PHOSPHODIESTERASE-4; TYPE-4; POTENT; IDENTIFICATION; OPTIMIZATION; RECOGNITION; MECHANISMS;

D O I：

10.1016/j.bmcl.2010.09.087

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC50 = 0.6 nM) displaying limited whole blood activity (IC50 = 555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：6387 / 6393

页数：7

共 39 条

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