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

Journal Article · Tue Feb 07 00:00:00 EST 2012 · Bioorg. Med. Chem. Lett.

DOI:https://doi.org/10.1016/j.bmcl.2010.10.034· OSTI ID:1025635

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 ^[1]

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1. BMS

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: INDUSTRY
• OSTI ID: 1025635
• Journal Information: Bioorg. Med. Chem. Lett., Vol. 20, Issue (23) ; 12, 2010
• Country of Publication: United States
• Language: ENGLISH

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