Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors
详细信息 查看全文
- 作者：Izzat T. Raheem ; Abbas M. Walji ; Daniel Klein ; John M. Sanders ; David A. Powell ; Pravien Abeywickrema ; Guillaume Barbe ; Amrith Bennet ; Sophie鈭扗orothee Clas ; David Dubost ; Mark Embrey ; Jay Grobler ; Michael J. Hafey ; Timothy J. Hartingh ; Daria J. Hazuda ; Michael D. Miller ; Keith P. Moore ; Natasa Pajkovic ; Sangita Patel ; Vanessa Rada ; Paul Rearden ; John D. Schreier ; John Sisko ; Thomas G. Steele ; Jean-Fran莽ois Truchon ; John Wai ; Min Xu ; Paul J. Coleman
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：October 22, 2015
- 年：2015
- 卷：58
- 期：20
- 页码：8154-8165
- 全文大小：705K
- ISSN：1520-4804
文摘
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.