Design, Synthesis, Biological Screening, and Molecular Docking Studies of Piperazine‐Derived Constrained Inhibitors of DPP‐IV for the Treatment of Type 2 Diabetes

Abstract

Novel piperazine-derived conformationally constrained compounds were designed, synthesized, and evaluated for in vitro Dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. From a library of compounds synthesized, 1-(2-(4-(7-Chloro-4-quinolyl)piperazin-1-yl)acetyl)pyrrolidine (2g) was identified as a potential DPP-IV inhibitor exhibiting better inhibitory activity than P32/98, reference inhibitor. The in vivo studies carried out in STZ and db/db mice models indicated that the compound 2g showed moderate antihyperglycemic activity as compared to the marketed drug Sitagliptin. A two-week repeated dose study in db/db mice revealed that compound 2g significantly declined blood glucose levels with no evidence of hypoglycemia risk. Furthermore, it showed improvement in insulin resistance reversal and antidyslipidemic properties. Molecular docking studies established good binding affinity of compound 2g at the DPP-IV active site and are in favor of the observed biological data. These data collectively suggest that compound 2g is a good lead molecule for further optimization studies.

Effect of Glycosin alkaloid from Rhizophora apiculata in non-insulin dependent diabetic rats and its mechanism of action: In vivo and in silico studies

“…The inhibition of DPP-IV prevents the inactivation of gastric inhibitory polypeptide and glucagon-like peptide-1. Activation of GLP-1 and GIP can stimulate insulin secretion, which results in lowering of glucose levels and improvement of the glycemic control (Kushwaha et al 2015). Insulin sensitivity to cells is attributed to phosphorylation of the insulin receptor, protein tyrosine phosphatase 1B, which dephosphorylates the tyrosine residues of IR proteins, is primarily responsible for insulin resistance in T2DM (Jung et al 2013).…”

Modified human glucagon-like peptide-1 (GLP-1) produced in E. coli has a long-acting therapeutic effect in type 2 diabetic mice

“…In order to overcome the short half-life of GLP-1 in the bloodstream, studies have mainly focused on identifying and developing DPP-IV inhibitors [ 20 , 21 ], modifying the structure of GLP-1, or searching for structural analogues that are more resistant to DPPIV cleavage [ 22 ]. Based on these studies, and the functional form of native GLP-1(7–36), a modified human GLP-1 (mGLP-1) was designed and constructed by site-specific mutations that would have resistance to both DPP-IV and trypsin cleavage.…”

Computational Analysis of Gynura bicolor Bioactive Compounds as Dipeptidyl Peptidase-IV Inhibitor

“…These data showed that G. bicolor bioactive compounds have comparable free-binding energy as observed for gliptin drugs. Gliptin drugs have been widely used as a positive control for DPPIV inhibitory experiments [ 10 , 62 ]. Among the gliptin drugs, anagliptin is believed to have the best half-maximal inhibitory concentration (IC 50 ) values when compared with sitagliptin and alogliptin [ 63 ].…”