3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma
| Autor: | James P. Rizzi, Xinlin Du, John A. Josey, Eli M. Wallace, Robert M. Czerwinski, Guangzhou Han, Rui Xu, Hanbiao Yang, Tai Wong, Shanhai Xie, Jonas Grina, Paul M. Wehn, Darryl D. Dixon, Stephen T. Schlachter, Emily L Ged, Keshi Wang, Heli Huang, Huiling Tan, Bin Wang |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Metabolite Glucuronidation Pharmacology medicine.disease 01 natural sciences 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound Clear cell renal cell carcinoma chemistry Hypoxia-inducible factors Pharmacokinetics Drug Discovery medicine Molecular Medicine Potency Glucuronide Drug metabolism 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 62:6876-6893 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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