化学
药代动力学
缺氧诱导因子
效力
药理学
葡萄糖醛酸化
代谢物
葡萄糖醛酸
生物化学
微粒体
体外
医学
基因
作者
Rui Xu,Keshi Wang,James P. Rizzi,Heli Huang,Jonas Grina,Stephen T. Schlachter,Bin Wang,Paul M. Wehn,Hanbiao Yang,Darryl D. Dixon,Robert Czerwiński,Xiaoqiang Du,Emily L. Ged,Guangzhou Han,Huiling Tan,Tai W. Wong,Shanhai Xie,John A. Josey,Eli M. Wallace
标识
DOI:10.1021/acs.jmedchem.9b00719
摘要
The hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Our first HIF-2α inhibitor PT2385 demonstrated promising proof of concept clinical activity in heavily pretreated advanced ccRCC patients. However, PT2385 was restricted by variable and dose-limited pharmacokinetics resulting from extensive metabolism of PT2385 to its glucuronide metabolite. Herein we describe the discovery of second-generation HIF-2α inhibitor PT2977 with increased potency and improved pharmacokinetic profile achieved by reduction of phase 2 metabolism. Structural modification by changing the geminal difluoro group in PT2385 to a vicinal difluoro group resulted in enhanced potency, decreased lipophilicity, and significantly improved pharmacokinetic properties. In a phase 1 dose-escalation study, the clinical pharmacokinetics for PT2977 supports the hypothesis that attenuating the rate of glucuronidation would improve exposure and reduce variability in patients. Early evidence of clinical activity shows promise for PT2977 in the treatment of ccRCC.
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