(1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: A Wingless β-Catenin Agonist That Increases Bone Formation Rate

被引：40

作者：

Pelletier, Jeffrey C. ^{[1
]}

Lundquist, Joseph T., IV ^{[1
]}

Gilbert, Adam M. ^{[4
]}

Alon, Nipa ^{[4
]}

Bex, Frederick J. ^{[2
]}

Bhat, Bheem M. ^{[2
]}

Bursavich, Mattew G. ^{[4
]}

Coleburn, Valerie E. ^{[2
]}

Felix, Luciana A. ^{[1
]}

Green, Daniel M. ^{[1
]}

Green, Paula ^{[2
]}

Hauze, Diane B. ^{[1
]}

Kharode, Yogendra P. ^{[2
]}

Lam, Ho-Sun ^{[2
]}

Lockhead, Susan R. ^{[3
]}

Magolda, Ronald L. ^{[1
]}

Matteo, Jeanne J. ^{[2
]}

Mehlmann, John F. ^{[1
]}

Milligan, Colleen ^{[2
]}

Murrills, Richard J. ^{[2
]}

Pirrello, Jennifer ^{[2
]}

Selim, Sally ^{[2
]}

Sharp, Michael C. ^{[2
]}

Unwalla, Ray J. ^{[1
]}

Vera, Matthew D. ^{[1
]}

Wrobel, Jay E. ^{[1
]}

Yaworsky, Paul ^{[2
]}

Bodine, Peter V. N. ^{[2
]}

机构：

[1] Wyeth Res, Chem Sci, Collegeville, PA 19426 USA

[2] Wyeth Res, Tissue Repair, Collegeville, PA 19426 USA

[3] Wyeth Res, Drug Safety & Metab, Collegeville, PA 19426 USA

[4] Wyeth Res, Chem Sci, Pearl River, NY 10965 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 22期

关键词：

WNT; MUTATION; PATHWAY; OSTEOPOROSIS; INHIBITORS; PROTEINS;

D O I：

10.1021/jm9014197

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.

引用

页码：6962 / 6965

页数：4

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