第二部分：作为强效、选择性和口服有效的 p38alpha 丝裂原活化蛋白激酶抑制剂的稠合吡唑的结构-活性关系（SAR）研究。
Part 2: Structure-activity relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase.
机构信息
Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
出版信息
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1680-4. doi: 10.1016/j.bmcl.2010.01.059. Epub 2010 Jan 21.
A novel class of pyrazolopyridazine p38alpha mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC(50) values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38alpha inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38alpha/beta over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of ca. 0.08mg/kg.
本发明公开了一类新型吡唑并哒嗪 p38α 丝裂原活化蛋白激酶（MAPK）抑制剂。进行了构效关系（SAR）研究，这些化合物具有抑制 p38α 酶、脂多糖刺激的 THP1 细胞系中 TNFα 的分泌以及在存在 50%人全血（hWB）的情况下抑制 TNFα 诱导的 IL-8 产生的能力。该研究发现了几种在 hWB 中具有个位数纳摩尔范围的 IC50 值的抑制剂。对这些先导化合物的药代动力学特征的进一步研究导致了三种有效且可口服生物利用的 p38α 抑制剂 2h、2m 和 13h 的鉴定。在 Ambit 筛选中，抑制剂 2m 被发现对 p38α/β 具有高度选择性，超过 402 种其他激酶，并且在 LPS 刺激的 Lewis 大鼠中对 TNFα 产生的抑制具有高度疗效，ED50 约为 0.08mg/kg。
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