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Design, Synthesis, Biological Screening, and Molecular Docking Studies of Piperazine‐Derived Constrained Inhibitors of DPP‐IV for the Treatment of Type 2 Diabetes
Author(s) -
Kushwaha Ram N.,
Srivastava Rohit,
Mishra Akansha,
Rawat Arun K.,
Srivastava Arvind K.,
Haq Wahajul,
Katti Seturam B.
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12426
Subject(s) - sitagliptin , piperazine , chemistry , docking (animal) , in vivo , pharmacology , lead compound , in vitro , insulin resistance , hypoglycemia , vildagliptin , stereochemistry , combinatorial chemistry , type 2 diabetes , insulin , diabetes mellitus , biochemistry , medicine , endocrinology , biology , nursing , microbiology and biotechnology
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.