Pettus Liping H, Xu Shimin, Cao Guo-Qiang, Chakrabarti Partha P, Rzasa Robert M, Sham Kelvin, Wurz Ryan P, Zhang Dawei, Middleton Scott, Henkle Bradley, Plant Matthew H, Saris Christiaan J M, Sherman Lisa, Wong Lu Min, Powers David A, Tudor Yanyan, Yu Violeta, Lee Matthew R, Syed Rashid, Hsieh Faye, Tasker Andrew S
Department of Chemistry Research and Discovery, Amgen Inc., Thousand Oaks, California 91320, USA.
J Med Chem. 2008 Oct 23;51(20):6280-92. doi: 10.1021/jm8005405. Epub 2008 Sep 26.
The p38 mitogen-activated protein kinase (MAPK) is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, osteoporosis, and many other diseases where aberrant cytokine signaling is the driver of disease. Herein, we describe a novel class of 3-amino-7-phthalazinylbenzoisoxazole-based inhibitors. With relatively low molecular weight, these compounds are highly potent in enzyme and cell-based assays, with minimal protein shift in 50% human whole blood. Compound 3c was efficacious (ED 50 = 0.05 mg/kg) in the rat collagen induced arthritis (CIA) model.
p38丝裂原活化蛋白激酶（MAPK）是许多促炎信号通路中的核心信号分子，可调节细胞对多种外部刺激的反应，包括热、紫外线辐射、渗透压休克以及多种细胞因子，尤其是白细胞介素-1β和肿瘤坏死因子α。因此，推测该酶的抑制剂在治疗类风湿性关节炎、炎症性肠病、骨质疏松症以及许多其他以异常细胞因子信号传导为疾病驱动因素的疾病方面具有显著的治疗潜力。在此，我们描述了一类新型的基于3-氨基-7-酞嗪基苯并异恶唑的抑制剂。这些化合物分子量相对较低，在酶和细胞实验中具有高效性，在50%人全血中的蛋白迁移最小。化合物3c在大鼠胶原诱导性关节炎（CIA）模型中有效（ED50 = 0.05 mg/kg）。
