吡唑并嘧啶类：一种用于高效选择性p38α抑制剂的新型杂环骨架。
Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors.
作者信息
Das Jagabandhu, Moquin Robert V, Pitt Sidney, Zhang Rosemary, Shen Ding Ren, McIntyre Kim W, Gillooly Kathleen, Doweyko Arthur M, Sack John S, Zhang Hongjian, Kiefer Susan E, Kish Kevin, McKinnon Murray, Barrish Joel C, Dodd John H, Schieven Gary L, Leftheris Katerina
机构信息
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
出版信息
Bioorg Med Chem Lett. 2008 Apr 15;18(8):2652-7. doi: 10.1016/j.bmcl.2008.03.019. Epub 2008 Mar 10.
The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
描述了基于吡唑并嘧啶支架的p38α丝裂原活化蛋白激酶（MAP激酶）抑制剂的合成及其构效关系（SAR）。这些研究导致鉴定出化合物2x是一种有效的、选择性的p38α MAP激酶抑制剂，对抑制TNFα产生具有优异的细胞活性。在急性TNFα产生的小鼠模型中，化合物2x在体内抑制TNFα产生方面具有高效性。还公开了与未磷酸化的p38α结合的吡唑并嘧啶类似物2b的X射线共晶体学研究结果。
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