Design, Synthesis, and Anti-inflammatory Properties of Orally Active 4-(Phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38α Mitogen-Activated Protein Kinase Inhibitors

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• 作者：John Hynes Jr. ; Alaric J. Dyckman ; Shuqun Lin ; Stephen T. Wrobleski ; Hong Wu ; Kathleen M. Gillooly ; Steven B. Kanner ; Herinder Lonial ; Derek Loo ; Kim W. McIntyre ; Sidney Pitt ; Ding Ren Shen ; David J.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：January 10, 2008
• 年：2008
• 卷：51
• 期：1
• 页码：4 - 16
• 全文大小：505K
• 年卷期：v.51,no.1(January 10, 2008)
• ISSN：1520-4804

文摘

A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1-f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC₅₀ 60 nM) and was active in a cell-based TNFα biosynthesis inhibition assay (IC₅₀ 210 nM). Replacement of the C4 oxindole with 2-methyl-5-N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC₅₀ 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1-f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFα). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.