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Title: 5-Amino-pyrazoles as potent and selective p38[alpha] inhibitors

Abstract

The synthesis and structure-activity relationships (SAR) of p38{alpha} 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 p38{alpha} MAP kinase with excellent cellular potency toward the inhibition of TNF{alpha} production. Compound 2j was highly efficacious in vivo in inhibiting TNF{alpha} production in an acute murine model of TNF{alpha} production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38{alpha} is also disclosed.

Authors:
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  1. BMS
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1025635
Resource Type:
Journal Article
Journal Name:
Bioorg. Med. Chem. Lett.
Additional Journal Information:
Journal Volume: 20; Journal Issue: (23) ; 12, 2010
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; IN VIVO; PHOSPHOTRANSFERASES; PRODUCTION; STRUCTURE-ACTIVITY RELATIONSHIPS; SYNTHESIS

Citation Formats

Das, Jagabandhu, Moquin, Robert V, Dyckman, Alaric J, Li, Tianle, Pitt, Sidney, Zhang, Rosemary, Shen, Ding Ren, McIntyre, Kim W, Gillooly, Kathleen, Doweyko, Arthur M, Newitt, John A, Sack, John S, Zhang, Hongjian, Kiefer, Susan E, Kish, Kevin, McKinnon, Murray, Barrish, Joel C, Dodd, John H, Schieven, Gary L, and Leftheris, Katerina. 5-Amino-pyrazoles as potent and selective p38[alpha] inhibitors. United States: N. p., 2012. Web. doi:10.1016/j.bmcl.2010.10.034.
Das, Jagabandhu, Moquin, Robert V, Dyckman, Alaric J, Li, Tianle, Pitt, Sidney, Zhang, Rosemary, Shen, Ding Ren, McIntyre, Kim W, Gillooly, Kathleen, Doweyko, Arthur M, Newitt, John A, Sack, John S, Zhang, Hongjian, Kiefer, Susan E, Kish, Kevin, McKinnon, Murray, Barrish, Joel C, Dodd, John H, Schieven, Gary L, & Leftheris, Katerina. 5-Amino-pyrazoles as potent and selective p38[alpha] inhibitors. United States. https://doi.org/10.1016/j.bmcl.2010.10.034
Das, Jagabandhu, Moquin, Robert V, Dyckman, Alaric J, Li, Tianle, Pitt, Sidney, Zhang, Rosemary, Shen, Ding Ren, McIntyre, Kim W, Gillooly, Kathleen, Doweyko, Arthur M, Newitt, John A, Sack, John S, Zhang, Hongjian, Kiefer, Susan E, Kish, Kevin, McKinnon, Murray, Barrish, Joel C, Dodd, John H, Schieven, Gary L, and Leftheris, Katerina. 2012. "5-Amino-pyrazoles as potent and selective p38[alpha] inhibitors". United States. https://doi.org/10.1016/j.bmcl.2010.10.034.
@article{osti_1025635,
title = {5-Amino-pyrazoles as potent and selective p38[alpha] inhibitors},
author = {Das, Jagabandhu and Moquin, Robert V and Dyckman, Alaric J and Li, Tianle and Pitt, Sidney and Zhang, Rosemary and Shen, Ding Ren and McIntyre, Kim W and Gillooly, Kathleen and Doweyko, Arthur M and Newitt, John A and Sack, John S and Zhang, Hongjian and Kiefer, Susan E and Kish, Kevin and McKinnon, Murray and Barrish, Joel C and Dodd, John H and Schieven, Gary L and Leftheris, Katerina},
abstractNote = {The synthesis and structure-activity relationships (SAR) of p38{alpha} 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 p38{alpha} MAP kinase with excellent cellular potency toward the inhibition of TNF{alpha} production. Compound 2j was highly efficacious in vivo in inhibiting TNF{alpha} production in an acute murine model of TNF{alpha} production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38{alpha} is also disclosed.},
doi = {10.1016/j.bmcl.2010.10.034},
url = {https://www.osti.gov/biblio/1025635}, journal = {Bioorg. Med. Chem. Lett.},
number = (23) ; 12, 2010,
volume = 20,
place = {United States},
year = {Tue Feb 07 00:00:00 EST 2012},
month = {Tue Feb 07 00:00:00 EST 2012}
}