Discovery of [(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonic acid, a potent and orally active small molecule PTP1B inhibitor
- 作者：Yongxin Han ; Michel Belley ; Christopher I. Bayly ; John Colucci ; Claude Dufresne ; Andre Giroux ; Cheuk K. Lau ; Yves Leblanc ; Daniel McKay ; Michel Therien ; Marie-Claire Wilson ; Kathryn Skorey ; Chi-Chung
- 关键词：Quinoline/naphthalene-difluoromethylphosphonate ; PTP1B inhibitors ; Diabetes ; Obesity ; Cancer
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2008
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：1 June 2008
- 卷：18
- 期：11
- 页码：3200-3205
- 文件大小：299 K
摘要
A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer.