Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38α MAP kinase inhibitors

Stephen T. Wrobleski; Shuqun Lin; John Hynes; Hong Wu; Sidney Pitt; Ding Ren Shen; Rosemary Zhang; Kathleen M. Gillooly; David J. Shuster; Kim W. McIntyre; Arthur M. Doweyko; Kevin F. Kish; Jeffrey A. Tredup; Gerald J. Duke; John S. Sack; Murray McKinnon; John Dodd; Joel C. Barrish; Gary L. Schieven; Katerina Leftheris

doi:10.1016/j.bmcl.2008.02.067

Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38α MAP kinase inhibitors

Stephen T. Wrobleski, Shuqun Lin, John Hynes, Hong Wu, Sidney Pitt, Ding Ren Shen, Rosemary Zhang, Kathleen M. Gillooly, David J. Shuster, Kim W. McIntyre, Arthur M. Doweyko, Kevin F. Kish, Jeffrey A. Tredup, Gerald J. Duke, John S. Sack, Murray McKinnon, John Dodd, Joel C. Barrish, Gary L. Schieven, Katerina Leftheris

Chemistry

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38 Scopus citations

Abstract

A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38α MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38α enzyme.

Original language	English (US)
Pages (from-to)	2739-2744
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	8
DOIs	https://doi.org/10.1016/j.bmcl.2008.02.067
State	Published - Apr 15 2008

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2008.02.067

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Wrobleski, S. T., Lin, S., Hynes, J., Wu, H., Pitt, S., Shen, D. R., Zhang, R., Gillooly, K. M., Shuster, D. J., McIntyre, K. W., Doweyko, A. M., Kish, K. F., Tredup, J. A., Duke, G. J., Sack, J. S., McKinnon, M., Dodd, J., Barrish, J. C., Schieven, G. L., & Leftheris, K. (2008). Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38α MAP kinase inhibitors. Bioorganic and Medicinal Chemistry Letters, 18(8), 2739-2744. https://doi.org/10.1016/j.bmcl.2008.02.067

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title = "Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38α MAP kinase inhibitors",

abstract = "A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38α MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38α enzyme.",

author = "Wrobleski, {Stephen T.} and Shuqun Lin and John Hynes and Hong Wu and Sidney Pitt and Shen, {Ding Ren} and Rosemary Zhang and Gillooly, {Kathleen M.} and Shuster, {David J.} and McIntyre, {Kim W.} and Doweyko, {Arthur M.} and Kish, {Kevin F.} and Tredup, {Jeffrey A.} and Duke, {Gerald J.} and Sack, {John S.} and Murray McKinnon and John Dodd and Barrish, {Joel C.} and Schieven, {Gary L.} and Katerina Leftheris",

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Wrobleski, ST, Lin, S, Hynes, J, Wu, H, Pitt, S, Shen, DR, Zhang, R, Gillooly, KM, Shuster, DJ, McIntyre, KW, Doweyko, AM, Kish, KF, Tredup, JA, Duke, GJ, Sack, JS, McKinnon, M, Dodd, J, Barrish, JC, Schieven, GL & Leftheris, K 2008, 'Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38α MAP kinase inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 8, pp. 2739-2744. https://doi.org/10.1016/j.bmcl.2008.02.067

TY - JOUR

T1 - Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38α MAP kinase inhibitors

AU - Wrobleski, Stephen T.

AU - Lin, Shuqun

AU - Hynes, John

AU - Wu, Hong

AU - Pitt, Sidney

AU - Shen, Ding Ren

AU - Zhang, Rosemary

AU - Gillooly, Kathleen M.

AU - Shuster, David J.

AU - McIntyre, Kim W.

AU - Doweyko, Arthur M.

AU - Kish, Kevin F.

AU - Tredup, Jeffrey A.

AU - Duke, Gerald J.

AU - Sack, John S.

AU - McKinnon, Murray

AU - Dodd, John

AU - Barrish, Joel C.

AU - Schieven, Gary L.

AU - Leftheris, Katerina

PY - 2008/4/15

Y1 - 2008/4/15

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AB - A novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38α MAP kinase inhibitors. The synthesis, structure-activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38α enzyme.

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ER -

Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38α MAP kinase inhibitors

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