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

• Published in: Chemical biology & drug design 2015-04, Vol.85 (4), p.439-446
• Main Authors: Kushwaha, Ram N., Srivastava, Rohit, Mishra, Akansha, Rawat, Arun K., Srivastava, Arvind K., Haq, Wahajul, Katti, Seturam B.
• Format: Article
• Language: English
• Subjects: Animals; antihyperglycemic; Blood Glucose - metabolism; constrained DPP-IV inhibitor; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - metabolism; Dipeptidyl Peptidase 4 - metabolism; dipeptidyl peptidyl-IV (DPP-IV) inhibitor; Dipeptidyl-Peptidase IV Inhibitors - chemical synthesis; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - therapeutic use; Mice; molecular docking; Molecular Docking Simulation; oral glucose tolerance test; piperazine; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - therapeutic use; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - therapeutic use
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12426

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. The piperazine‐derived constrained compound, 2g was identified as a potent DPP‐IV inhibitor having good antidiabetic, antidyslipidemic and insulin resistance reversal properties. Molecular docking is in favor of observed biological activity.