Discovery of Selective 4-Amino-pyridopyrimidine Inhibitors of MAP4K4 Using Fragment-Based Lead Identification and Optimization

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• 作者：Terry D. Crawford ; Chudi O. Ndubaku ; Huifen Chen ; Jason W. Boggs ; Brandon J. Bravo ; Kelly DeLaTorre ; Anthony M. Giannetti ; Stephen E. Gould ; Seth F. Harris ; Steven R. Magnuson ; Erin McNamara ; Lesley J. Murray ; Jim Nonomiya ; Amy Sambrone ; Stephen Schmidt ; Tanya Smyczek ; Mark Stanley ; Philip Vitorino ; Lan Wang ; Kristina West ; Ping Wu ; Weilan Ye
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3484-3493
• 全文大小：462K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.