Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment
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- 作者：Mark Ammirati ; Scott W. Bagley ; Samit K. Bhattacharya ; Leonard Buckbinder ; Anthony A. Carlo ; Rebecca Conrad ; Christian Cortes ; Robert L. Dow ; Matthew S. Dowling ; Ayman El-Kattan ; Kristen Ford ; Cristiano R. W. Guimar茫es ; David Hepworth ; Wenhua Jiao ; Jennifer LaPerle ; Shenping Liu ; Allyn Londregan ; Paula M. Loria ; Alan M. Mathiowetz ; Michael Munchhof ; Suvi T. M. Orr ; Donna N. Petersen ; David A. Price ; Athanasia Skoura ; Aaron C. Smith ; Jian Wang
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2015
- 出版时间：November 12, 2015
- 年：2015
- 卷：6
- 期：11
- 页码：1128-1133
- 全文大小：398K
- ISSN：1948-5875
文摘
Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.