Design, synthesis of lithocholic acid mimics and their inhibitory activities against protein tyrosine phosphatase 1B

Protein tyrosine phosphatase-1B (PTP1B), a negative regulatory factor of insulin signaling, is recognized as a potent target for the therapy of diabetes. Aimed to provide new scaffold to the development of PTP1B inhibitors and disclose the relationship between configurations of certain positions (3, 4, 5, 6 and 23-position) on the steroidal skeleton and inhibitory activities against PTP1B, a class of lithocholic acid (LCA) mimics were designed and synthesized. In vitro bioassay against PTP1B showed that 3β-hydroxy-4-ene-cholanic acid (17) and 4,4-dimethyl-3β-hydroxy-5-ene-cholanic acid (19) had activities higher than LCA, reaching (8.50±1.21) and (6.27±1.03) μmol•L-1, respectively. Docking analysis of compounds 17 and 19 illuminated the binding modes to PTP1B. This study provided compounds with new scaffold and valuable structure- activity-relationship (SAR) information for the further study of PTP1B inhibitors.