一种强效、选择性且口服生物可利用的c-Met抑制剂的发现：1-(2-羟基-2-甲基丙基)-N-(5-(7-甲氧基喹啉-4-基氧基)吡啶-2-基)-5-甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺（AMG 458）。
Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458).
作者信息
Liu Longbin, Siegmund Aaron, Xi Ning, Kaplan-Lefko Paula, Rex Karen, Chen April, Lin Jasmine, Moriguchi Jodi, Berry Loren, Huang Liyue, Teffera Yohannes, Yang Yajing, Zhang Yihong, Bellon Steven F, Lee Matthew, Shimanovich Roman, Bak Annette, Dominguez Celia, Norman Mark H, Harmange Jean-Christophe, Dussault Isabelle, Kim Tae-Seong
机构信息
Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
出版信息
J Med Chem. 2008 Jul 10;51(13):3688-91. doi: 10.1021/jm800401t. Epub 2008 Jun 14.
Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, nonselective metabolites. Blocking this metabolic hot spot led to the discovery of 17 (AMG 458). When dosed orally, 17 significantly inhibited tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.
受体酪氨酸激酶c-Met的失调与人类癌症有关。N-1位带有侧链羟烷基的吡唑啉酮对c-Met的抑制作用比对VEGFR2更具选择性。然而，研究发现会生成活性的、非选择性的代谢产物。阻断这一代谢热点促使发现了化合物17（AMG 458）。口服给药时，化合物17在NIH3T3/TPR-Met和U-87 MG异种移植模型中显著抑制肿瘤生长，且对体重无不良影响。
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