A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agent

Abstract

Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin-secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue. DSC108 increased the intracellular Ca2+ level in MIN6-K8 cells. Competitive inhibition experiment and electrophysiological analysis revealed sulfonylurea receptor 1 (SUR1) to be the target of DSC108 and that this diphenylthiosemicarbazide directly inhibits ATP-sensitive K+ (KATP) channels. Pharmacokinetic analysis showed that DSC108 has a short half-life in vivo. Oral administration of DSC108 significantly suppressed the rises in blood glucose levels after glucose load in wild-type mice and improved glucose tolerance in the Goto-Kakizaki (GK) rat, a model of type 2 diabetes with impaired insulin secretion. Our data indicate that DSC108 is a novel insulin secretagogue, and is a lead compound for development of a new anti-diabetic agent.

β‐Cell signalling and insulin secretagogues: A path for improved diabetes therapy

“…In silico similarity search is a powerful method for retrieving compounds with characteristics similar to those of known ligands . We attempted to identify novel small molecules to stimulate insulin secretion by similarity search based on the information on the structures of sulfonylureas . For similarity search, two‐dimensional (2D) structures of various sulfonylureas were used as queries: 38 compounds were retrieved as candidate compounds from a commercially available database containing approximately 5 million compounds.…”

“…Identification of small molecules that stimulate insulin secretion by ligand‐based drug design (LBDD)‐based approach. An example of identification of the new insulin secretagogue DSC108 is shown in blue. See text for details…”