5-Amino-pyrazoles as potent and selective p38α inhibitors

Jagabandhu Das; Robert V. Moquin; Alaric J. Dyckman; Tianle Li; Sidney Pitt; Rosemary Zhang; Ding Ren Shen; Kim W. McIntyre; Kathleen Gillooly; Arthur M. Doweyko; John A. Newitt; John S. Sack; Hongjian Zhang; Susan E. Kiefer; Kevin Kish; Murray McKinnon; Joel C. Barrish; John H. Dodd; Gary L. Schieven; Katerina Leftheris

doi:10.1016/j.bmcl.2010.10.034

5-Amino-pyrazoles as potent and selective p38α inhibitors

Jagabandhu Das, Robert V. Moquin, Alaric J. Dyckman, Tianle Li, Sidney Pitt, Rosemary Zhang, Ding Ren Shen, Kim W. McIntyre, Kathleen Gillooly, Arthur M. Doweyko, John A. Newitt, John S. Sack, Hongjian Zhang, Susan E. Kiefer, Kevin Kish, Murray McKinnon, Joel C. Barrish, John H. Dodd, Gary L. Schieven, Katerina Leftheris

Chemistry

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

23 Scopus citations

Abstract

The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.

Original language	English (US)
Pages (from-to)	6886-6889
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2010.10.034
State	Published - Dec 1 2010

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.2010.10.034

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Das, J., Moquin, R. V., Dyckman, A. J., Li, T., Pitt, S., Zhang, R., Shen, D. R., McIntyre, K. W., Gillooly, K., Doweyko, A. M., Newitt, J. A., Sack, J. S., Zhang, H., Kiefer, S. E., Kish, K., McKinnon, M., Barrish, J. C., Dodd, J. H., Schieven, G. L., & Leftheris, K. (2010). 5-Amino-pyrazoles as potent and selective p38α inhibitors. Bioorganic and Medicinal Chemistry Letters, 20(23), 6886-6889. https://doi.org/10.1016/j.bmcl.2010.10.034

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title = "5-Amino-pyrazoles as potent and selective p38α inhibitors",

abstract = "The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.",

author = "Jagabandhu Das and Moquin, {Robert V.} and Dyckman, {Alaric J.} and Tianle Li and Sidney Pitt and Rosemary Zhang and Shen, {Ding Ren} and McIntyre, {Kim W.} and Kathleen Gillooly and Doweyko, {Arthur M.} and Newitt, {John A.} and Sack, {John S.} and Hongjian Zhang and Kiefer, {Susan E.} and Kevin Kish and Murray McKinnon and Barrish, {Joel C.} and Dodd, {John H.} and Schieven, {Gary L.} and Katerina Leftheris",

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doi = "10.1016/j.bmcl.2010.10.034",

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Das, J, Moquin, RV, Dyckman, AJ, Li, T, Pitt, S, Zhang, R, Shen, DR, McIntyre, KW, Gillooly, K, Doweyko, AM, Newitt, JA, Sack, JS, Zhang, H, Kiefer, SE, Kish, K, McKinnon, M, Barrish, JC, Dodd, JH, Schieven, GL & Leftheris, K 2010, '5-Amino-pyrazoles as potent and selective p38α inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 23, pp. 6886-6889. https://doi.org/10.1016/j.bmcl.2010.10.034

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T1 - 5-Amino-pyrazoles as potent and selective p38α inhibitors

AU - Das, Jagabandhu

AU - Moquin, Robert V.

AU - Dyckman, Alaric J.

AU - Li, Tianle

AU - Pitt, Sidney

AU - Zhang, Rosemary

AU - Shen, Ding Ren

AU - McIntyre, Kim W.

AU - Gillooly, Kathleen

AU - Doweyko, Arthur M.

AU - Newitt, John A.

AU - Sack, John S.

AU - Zhang, Hongjian

AU - Kiefer, Susan E.

AU - Kish, Kevin

AU - McKinnon, Murray

AU - Barrish, Joel C.

AU - Dodd, John H.

AU - Schieven, Gary L.

AU - Leftheris, Katerina

PY - 2010/12/1

Y1 - 2010/12/1

N2 - The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.

AB - The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.

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JO - Bioorganic and Medicinal Chemistry Letters

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IS - 23

ER -

5-Amino-pyrazoles as potent and selective p38α inhibitors

Abstract

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