3-Phenylpropanoic Acid-Based Phosphotyrosine (pTyr) Mimetics: Hit Evolution to a Novel Orally Active Protein Tyrosine Phosphatase1B (PTP1B) Inhibitor

• Published in: ChemMedChem 2014-05, Vol.9 (5), p.918
• Main Authors: Tang, Yan-Bo, Liu, Jun-Zheng, Zhang, Shu-En, Du, Xin, Nie, Feilin, Tian, Jin-Ying, Ye, Fei, Huang, Kai, Hu, Jin-Ping, Li, Yan, Xiao, Zhiyan
• Format: Article
• Language: English
• Subjects: Acids; Rodents
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201400007

Protein tyrosine phosphatase1B (PTP1B) is a promising therapeutic target for type2 diabetes. Herein, we report the evolution of a previously identified 3-phenylpropanoic acid-based PTP1B inhibitor to an orally active lead compound. A series of 3-phenylpropanoic acid-based PTP1B inhibitors were synthesized, and three of them, 3-(4-(9H-carbazol-9-yl)phenyl)-5-(3,5-di-tert-butyl-4-methoxyphenyl)-5-oxopentanoic acid (9), 3-(4-(9H-carbazol-9-yl)phenyl)-5-(4'-bromo-[1,1'-biphenyl]-4-yl)-5-oxopentanoic acid (10) and 3-(4-(9H-carbazol-9-yl)-2-fluorophenyl)-5-(4-cyclohexylphenyl)-5-oxopentanoic acid (16), showed IC50 values at sub-micromolar level. Further invivo evaluation indicated the sodium salt of 9 not only exhibited significant insulin-sensitizing and hypoglycemia effects, but also decreased the serum levels of triglyceride and total cholesterol in high-fat-diet-induced insulin resistance model mice. Preliminary invivo pharmacokinetic studies on the sodium salt of 9 revealed its pharmacokinetic profile after oral administration in rats. These results provide proof-of-concept for the dual effects of PTP1B inhibitors on both glucose and lipid metabolisms. [PUBLICATION ABSTRACT]