Type 2 diabetes mellitus (T2DM), a pervasive disease with wide-ranging effects on social well-being, is characterized by persistent hyperglycemia caused by impaired insulin action and β-cell function, leading to serious complications. The major risk factor associated with the development of T2DM is defective glucose-stimulated insulin secretion (GSIS) in pancreatic islets. In the clinical management of T2DM, there are several antidiabetic agents currently available. However, they elicit undesirable adverse effects such as hypoglycemia, heart failure, cholangiocarcinoma and weight gain. For these reasons, identifying new molecules and pathways which can lead to the normal blood sugar level through stimulation of GSIS is urgently needed. In an effort to develop novel antidiabetic agents, an in-house chemical library was screened using INS-1 cells with a GSIS assay. From the preliminary screening, we identified a hit compound which showed a considerably enhanced insulin secretion activity. Considering the structure of hit, we designed and synthesized a series of 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides by introducing various substituents on both benzene rings. Using two-step SAR approach, we discovered a highly potent compound with enhanced GSIS from β-cells without any cytotoxicity. Western blot analysis was performed to investigate the potential mechanism of the analog. The results suggested that the analog could exhibited the increase of GSIS which mediated through the activity of pancreatic and duodenal homeobox 1 (PDX-1), an important GSIS-promoting factor. Furthermore, the analog stimulates glucose uptake via suppression of Mitsugumin 53 (MG53), an E3 ligase which is responsible for the ubiquitination of insulin receptor substrate 1 (IRS-1) in C2C12 myotube cells.

SAR studies of novel 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamide derivatives as dual-acting antidiabetic agents

ACS Fall 2021

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