Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, USA.
Bioorg Med Chem Lett. 2010 Dec 1;20(23):6886-9. doi: 10.1016/j.bmcl.2010.10.034. Epub 2010 Oct 13.
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.
本文描述了基于 5-氨基-吡唑骨架的 p38α MAP 激酶抑制剂的合成和构效关系（SAR）。这些研究导致发现了化合物 2j，它是一种有效的 p38α MAP 激酶选择性抑制剂，对 TNFα 产生的抑制具有优异的细胞效力。化合物 2j 在体内急性 TNFα 产生的小鼠模型中抑制 TNFα 产生具有高度疗效。还披露了与未磷酸化的 p38α 结合的 5-氨基-吡唑类似物 2f 的 X 射线共结晶。
