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

John Hynes; 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; Ren Shen Ding; David J. Shuster; Xiao Xia Yang; Rosemary Zhang; Kamelia Behnia; Hongjian Zhang; Punit H. Marathe; Arthur M. Doweyko; John S. Tokarski; John S. Sack; Matthew Pokross; Susan E. Kiefer; John A. Newitt; Joel C. Barrish; John Dodd; Gary L. Schieven; Katerina Leftheris

doi:10.1021/jm7009414

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

John Hynes, 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, Ren Shen Ding, David J. Shuster, Xiao Xia Yang, Rosemary Zhang, Kamelia Behnia, Hongjian Zhang, Punit H. Marathe, Arthur M. Doweyko, John S. TokarskiJohn S. Sack, Matthew Pokross, Susan E. Kiefer, John A. Newitt, Joel C. Barrish, John Dodd, Gary L. Schieven, Katerina Leftheris

Chemistry

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73 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	4-16
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	1
DOIs	https://doi.org/10.1021/jm7009414
State	Published - Jan 10 2008

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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10.1021/jm7009414

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Hynes, J., Dyckman, A. J., Lin, S., Wrobleski, S. T., Wu, H., Gillooly, K. M., Kanner, S. B., Lonial, H., Loo, D., McIntyre, K. W., Pitt, S., Ding, R. S., Shuster, D. J., Yang, X. X., Zhang, R., Behnia, K., Zhang, H., Marathe, P. H., Doweyko, A. M., ... Leftheris, K. (2008). 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. Journal of Medicinal Chemistry, 51(1), 4-16. https://doi.org/10.1021/jm7009414

Hynes, John ; Dyckman, Alaric J. ; Lin, Shuqun ; Wrobleski, Stephen T. ; Wu, Hong ; Gillooly, Kathleen M. ; Kanner, Steven B. ; Lonial, Herinder ; Loo, Derek ; McIntyre, Kim W. ; Pitt, Sidney ; Ding, Ren Shen ; Shuster, David J. ; Yang, Xiao Xia ; Zhang, Rosemary ; Behnia, Kamelia ; Zhang, Hongjian ; Marathe, Punit H. ; Doweyko, Arthur M. ; Tokarski, John S. ; Sack, John S. ; Pokross, Matthew ; Kiefer, Susan E. ; Newitt, John A. ; Barrish, Joel C. ; Dodd, John ; Schieven, Gary L. ; Leftheris, Katerina. / 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. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 1. pp. 4-16.

@article{ef5110b6b06e44f7a0f50ae095002321,

title = "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",

abstract = "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.",

author = "John Hynes and Dyckman, {Alaric J.} and Shuqun Lin and Wrobleski, {Stephen T.} and Hong Wu and Gillooly, {Kathleen M.} and Kanner, {Steven B.} and Herinder Lonial and Derek Loo and McIntyre, {Kim W.} and Sidney Pitt and Ding, {Ren Shen} and Shuster, {David J.} and Yang, {Xiao Xia} and Rosemary Zhang and Kamelia Behnia and Hongjian Zhang and Marathe, {Punit H.} and Doweyko, {Arthur M.} and Tokarski, {John S.} and Sack, {John S.} and Matthew Pokross and Kiefer, {Susan E.} and Newitt, {John A.} and Barrish, {Joel C.} and John Dodd and Schieven, {Gary L.} and Katerina Leftheris",

year = "2008",

month = jan,

day = "10",

doi = "10.1021/jm7009414",

language = "English (US)",

volume = "51",

pages = "4--16",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "1",

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Hynes, J, Dyckman, AJ, Lin, S, Wrobleski, ST, Wu, H, Gillooly, KM, Kanner, SB, Lonial, H, Loo, D, McIntyre, KW, Pitt, S, Ding, RS, Shuster, DJ, Yang, XX, Zhang, R, Behnia, K, Zhang, H, Marathe, PH, Doweyko, AM, Tokarski, JS, Sack, JS, Pokross, M, Kiefer, SE, Newitt, JA, Barrish, JC, Dodd, J, Schieven, GL & Leftheris, K 2008, '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', Journal of Medicinal Chemistry, vol. 51, no. 1, pp. 4-16. https://doi.org/10.1021/jm7009414

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. / Hynes, John; Dyckman, Alaric J.; Lin, Shuqun; Wrobleski, Stephen T.; Wu, Hong; Gillooly, Kathleen M.; Kanner, Steven B.; Lonial, Herinder; Loo, Derek; McIntyre, Kim W.; Pitt, Sidney; Ding, Ren Shen; Shuster, David J.; Yang, Xiao Xia; Zhang, Rosemary; Behnia, Kamelia; Zhang, Hongjian; Marathe, Punit H.; Doweyko, Arthur M.; Tokarski, John S.; Sack, John S.; Pokross, Matthew; Kiefer, Susan E.; Newitt, John A.; Barrish, Joel C.; Dodd, John; Schieven, Gary L.; Leftheris, Katerina.

In: Journal of Medicinal Chemistry, Vol. 51, No. 1, 10.01.2008, p. 4-16.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Hynes, John

AU - Dyckman, Alaric J.

AU - Lin, Shuqun

AU - Wrobleski, Stephen T.

AU - Wu, Hong

AU - Gillooly, Kathleen M.

AU - Kanner, Steven B.

AU - Lonial, Herinder

AU - Loo, Derek

AU - McIntyre, Kim W.

AU - Pitt, Sidney

AU - Ding, Ren Shen

AU - Shuster, David J.

AU - Yang, Xiao Xia

AU - Zhang, Rosemary

AU - Behnia, Kamelia

AU - Zhang, Hongjian

AU - Marathe, Punit H.

AU - Doweyko, Arthur M.

AU - Tokarski, John S.

AU - Sack, John S.

AU - Pokross, Matthew

AU - Kiefer, Susan E.

AU - Newitt, John A.

AU - Barrish, Joel C.

AU - Dodd, John

AU - Schieven, Gary L.

AU - Leftheris, Katerina

PY - 2008/1/10

Y1 - 2008/1/10

N2 - 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.

AB - 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.

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U2 - 10.1021/jm7009414

DO - 10.1021/jm7009414

M3 - Article

C2 - 18072718

AN - SCOPUS:37849002831

VL - 51

SP - 4

EP - 16

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -

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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