Wurz Ryan P, Pettus Liping H, Xu Shimin, Henkle Bradley, Sherman Lisa, Plant Matthew, Miner Kent, McBride Helen, Wong Lu Min, Saris Christiaan J M, Lee Matthew R, Chmait Samer, Mohr Christopher, Hsieh Faye, Tasker Andrew S
Department of Chemistry Research & Discovery, Amgen Inc, Thousand Oaks, CA 91320, USA.
Bioorg Med Chem Lett. 2009 Aug 15;19(16):4724-8. doi: 10.1016/j.bmcl.2009.06.058. Epub 2009 Jun 17.
A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.
公开了一类新型的源自吡唑并稠合的p38α丝裂原活化蛋白激酶（MAPK）抑制剂。对这些抑制剂抑制p38α酶的能力、在LPS刺激的THP1细胞系中TNFα的分泌以及在50%人全血中TNFα诱导的IL-8产生进行了评估。通过构效关系（SAR）研究对该系列进行了优化，以提供在全血中IC(50)值处于低个位数纳摩尔范围的抑制剂。对其药代动力学特征的进一步研究导致鉴定出两种强效且口服生物可利用的p38抑制剂10 m和10 q。发现抑制剂10 m在体内对LPS刺激的Lewis大鼠中TNFα产生的抑制有效，ED(50)为0.1mg/kg，而10 q的ED(50)为0.05 - 0.07mg/kg。
