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发现用于治疗炎症性疾病的一流受体相互作用蛋白 1 (RIP1) 激酶特异性临床候选药物 (GSK2982772)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-02-10 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01751 Philip A Harris , Scott B Berger , Jae U Jeong , Rakesh Nagilla , Deepak Bandyopadhyay , Nino Campobasso , Carol A Capriotti , Julie A Cox , Lauren Dare , Xiaoyang Dong , Patrick M Eidam , Joshua N Finger , Sandra J Hoffman , James Kang , Viera Kasparcova , Bryan W King , Ruth Lehr , Yunfeng Lan , Lara K Leister , John D Lich , Thomas T MacDonald 1 , Nathan A Miller , Michael T Ouellette , Christina S Pao , Attiq Rahman , Michael A Reilly , Alan R Rendina , Elizabeth J Rivera , Michelle C Schaeffer , Clark A Sehon , Robert R Singhaus , Helen H Sun , Barbara A Swift , Rachel D Totoritis , Anna Vossenkämper 1 , Paris Ward , David D Wisnoski , Daohua Zhang , Robert W Marquis , Peter J Gough , John Bertin
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-02-10 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01751 Philip A Harris , Scott B Berger , Jae U Jeong , Rakesh Nagilla , Deepak Bandyopadhyay , Nino Campobasso , Carol A Capriotti , Julie A Cox , Lauren Dare , Xiaoyang Dong , Patrick M Eidam , Joshua N Finger , Sandra J Hoffman , James Kang , Viera Kasparcova , Bryan W King , Ruth Lehr , Yunfeng Lan , Lara K Leister , John D Lich , Thomas T MacDonald 1 , Nathan A Miller , Michael T Ouellette , Christina S Pao , Attiq Rahman , Michael A Reilly , Alan R Rendina , Elizabeth J Rivera , Michelle C Schaeffer , Clark A Sehon , Robert R Singhaus , Helen H Sun , Barbara A Swift , Rachel D Totoritis , Anna Vossenkämper 1 , Paris Ward , David D Wisnoski , Daohua Zhang , Robert W Marquis , Peter J Gough , John Bertin
Affiliation
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RIP1 调节坏死性凋亡和炎症，并可能在促成多种人类疾病（包括免疫介导的炎症性疾病）中发挥重要作用。适用于临床的 RIP1 激酶小分子抑制剂尚未被描述。在此，我们报告了我们对来自 DNA 编码库的苯并沙西酮命中的先导优化以及临床候选 GSK2982772（化合物5 ）的发现和概况，目前处于银屑病、类风湿性关节炎和溃疡性结肠炎的 2a 期临床研究中。化合物5以精细的激酶特异性有效地与 RIP1 结合，并在阻断许多 TNF 依赖性细胞反应方面具有出色的活性。该抑制剂突出了其作为新型抗炎剂的潜力，还能够减少人类溃疡性结肠炎外植体中细胞因子的自发产生。5的非常有利的物理化学和 ADMET 特性，再加上高效力，导致预计在人类中的口服剂量较低。
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更新日期：2017-02-10
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