title: 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.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, 226031, India.
authors.forename: Ram N
authors.initials: RN
authors.lastname: Kushwaha
authors.forename: Rohit
authors.initials: R
authors.lastname: Srivastava
authors.forename: Akansha
authors.initials: A
authors.lastname: Mishra
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rawat
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Srivastava
authors.forename: Wahajul
authors.initials: W
authors.lastname: Haq
authors.forename: Seturam B
authors.initials: SB
authors.lastname: Katti
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D062105:Molecular Docking Simulation; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010879:Piperazines; D011759:Pyrrolidines; D000077489:Piperazine; D018819:Dipeptidyl Peptidase 4; C032519:pyrrolidine
keywords: antihyperglycemic; constrained DPP-IV inhibitor; dipeptidyl peptidyl-IV (DPP-IV) inhibitor; molecular docking; oral glucose tolerance test; piperazine