Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia due to the reduction of sensitivity to insulin and the dysfunction of insulin-secreting in pancreatic beta-cells. The disease has been spread all over the world and affected over 300 million people. Although many anti-diabetic drugs are currently available to treat this chronic disease, they have limited long-term efficacy due to undesirable adverse effects. Hence, the strong need for novel anti-diabetic agents with a good safety still continues. In connection with development of novel hypoglycemic agents, a dose dependent GSIS assay was conducted in an INS-1 β cell line to screen a druggable in-house chemical library. We identified a potent hit compound with azacycle-based novel skeleton which showed equal insulin-secreting activity with that of gliclazide. The newly designed 40 azacycles were synthesized to develop more potent and safe analogs and then their biological activities were evaluated using GSIS and MTT assay on INS-1 β cells. From the structure-activity relationship (SAR) studies, the electron donating group which substituted in amidobenzene ring plays a crucial part in insulin-secreting activity. Furthermore, mechanism studies on most potent compound revealed that our compounds act as agonists on PPARγ receptor.

Discovery and SAR studies of novel non-toxic azacyclic derivatives for the treatment of type 2 diabetes mellitus

2019 Spring National Meeting

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