Highlights

Novel 41 compounds of 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides were designed, synthesized, and biologically evaluated.

Compound 26 showed the highest GSI value.

Western blotting assay suggested 26 increase GSIS by regulating PDX-1 activity in INS-1 cells.

26 could augment glucose uptake in C2C12 myotube cells through suppressing MG53 expression.

Abstract

A novel series of 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides was designed, synthesized and evaluated for their biological activities on glucose-stimulated insulin secretion (GSIS). The cytotoxicity of all 41 novel compounds was screened to assess their pharmacological safety in pancreatic β-cells. A two-step optimization process was carried out to establish the structure-activity relationship for this class and subsequently we identified the most active analogue 26. Further modification study of 26 evidenced the necessity of N-hydrogens in the core architecture. Protein expression analysis suggested that 26 increases insulin secretion via the activation of the upstream effector of pancreatic and duodenal homeobox 1 (PDX-1), which is an important factor promoting GSIS. Moreover, the administration of 26 effectively augmented glucose uptake in C2C12 myotube cells via the suppression of Mitsugumin 53 (MG53), an insulin receptor substrate 1 (IRS-1) ubiquitination E3 ligase.