Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

Chunjian Liu; James Lin; Stephen T. Wrobleski; Shuqun Lin; John Hynes; Hong Wu; Alaric J. Dyckman; Tianle Li; John Wityak; Kathleen M. Gillooly; Sidney Pitt; Ding Ren Shen; Rosemary F. Zhang; Kim W. McIntyre; Luisa Salter-Cid; David J. Shuster; Hongjian Zhang; Punit H. Marathe; Arthur M. Doweyko; John S. Sack; Susan E. Kiefer; Kevin F. Kish; John A. Newitt; Murray McKinnon; John H. Dodd; Joel C. Barrish; Gary L. Schieven; Katerina Leftheris

doi:10.1021/jm100540x

Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

Chunjian Liu, James Lin, Stephen T. Wrobleski, Shuqun Lin, John Hynes, Hong Wu, Alaric J. Dyckman, Tianle Li, John Wityak, Kathleen M. Gillooly, Sidney Pitt, Ding Ren Shen, Rosemary F. Zhang, Kim W. McIntyre, Luisa Salter-Cid, David J. Shuster, Hongjian Zhang, Punit H. Marathe, Arthur M. Doweyko, John S. SackSusan E. Kiefer, Kevin F. Kish, John A. Newitt, Murray McKinnon, John H. Dodd, Joel C. Barrish, Gary L. Schieven, Katerina Leftheris

Chemistry

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Abstract

The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp² character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.

Original language	English (US)
Pages (from-to)	6629-6639
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	18
DOIs	https://doi.org/10.1021/jm100540x
State	Published - Sep 23 2010

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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Liu, C., Lin, J., Wrobleski, S. T., Lin, S., Hynes, J., Wu, H., Dyckman, A. J., Li, T., Wityak, J., Gillooly, K. M., Pitt, S., Shen, D. R., Zhang, R. F., McIntyre, K. W., Salter-Cid, L., Shuster, D. J., Zhang, H., Marathe, P. H., Doweyko, A. M., ... Leftheris, K. (2010). Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases. Journal of Medicinal Chemistry, 53(18), 6629-6639. https://doi.org/10.1021/jm100540x

@article{6f0c2d3b485a488683497dd396fac6d0,

title = "Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases",

abstract = "The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp2 character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.",

author = "Chunjian Liu and James Lin and Wrobleski, {Stephen T.} and Shuqun Lin and John Hynes and Hong Wu and Dyckman, {Alaric J.} and Tianle Li and John Wityak and Gillooly, {Kathleen M.} and Sidney Pitt and Shen, {Ding Ren} and Zhang, {Rosemary F.} and McIntyre, {Kim W.} and Luisa Salter-Cid and Shuster, {David J.} and Hongjian Zhang and Marathe, {Punit H.} and Doweyko, {Arthur M.} and Sack, {John S.} and Kiefer, {Susan E.} and Kish, {Kevin F.} and Newitt, {John A.} and Murray McKinnon and Dodd, {John H.} and Barrish, {Joel C.} and Schieven, {Gary L.} and Katerina Leftheris",

year = "2010",

month = sep,

day = "23",

doi = "10.1021/jm100540x",

language = "English (US)",

volume = "53",

pages = "6629--6639",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "18",

}

Liu, C, Lin, J, Wrobleski, ST, Lin, S, Hynes, J, Wu, H, Dyckman, AJ, Li, T, Wityak, J, Gillooly, KM, Pitt, S, Shen, DR, Zhang, RF, McIntyre, KW, Salter-Cid, L, Shuster, DJ, Zhang, H, Marathe, PH, Doweyko, AM, Sack, JS, Kiefer, SE, Kish, KF, Newitt, JA, McKinnon, M, Dodd, JH, Barrish, JC, Schieven, GL & Leftheris, K 2010, 'Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases', Journal of Medicinal Chemistry, vol. 53, no. 18, pp. 6629-6639. https://doi.org/10.1021/jm100540x

Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases. / Liu, Chunjian; Lin, James; Wrobleski, Stephen T. et al.
In: Journal of Medicinal Chemistry, Vol. 53, No. 18, 23.09.2010, p. 6629-6639.

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

TY - JOUR

T1 - Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

AU - Liu, Chunjian

AU - Lin, James

AU - Wrobleski, Stephen T.

AU - Lin, Shuqun

AU - Hynes, John

AU - Wu, Hong

AU - Dyckman, Alaric J.

AU - Li, Tianle

AU - Wityak, John

AU - Gillooly, Kathleen M.

AU - Pitt, Sidney

AU - Shen, Ding Ren

AU - Zhang, Rosemary F.

AU - McIntyre, Kim W.

AU - Salter-Cid, Luisa

AU - Shuster, David J.

AU - Zhang, Hongjian

AU - Marathe, Punit H.

AU - Doweyko, Arthur M.

AU - Sack, John S.

AU - Kiefer, Susan E.

AU - Kish, Kevin F.

AU - Newitt, John A.

AU - McKinnon, Murray

AU - Dodd, John H.

AU - Barrish, Joel C.

AU - Schieven, Gary L.

AU - Leftheris, Katerina

PY - 2010/9/23

Y1 - 2010/9/23

N2 - The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp2 character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.

AB - The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp2 character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.

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UR - http://www.scopus.com/inward/citedby.url?scp=77956738797&partnerID=8YFLogxK

U2 - 10.1021/jm100540x

DO - 10.1021/jm100540x

M3 - Article

C2 - 20804198

AN - SCOPUS:77956738797

SN - 0022-2623

VL - 53

SP - 6629

EP - 6639

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -

Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N- propylpyrrolo[1,2-f ][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases

Abstract

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