title: Pharmacological characterization of ZYDPLA1, a novel long-acting dipeptidyl peptidase-4 inhibitor.
abstract: OBJECTIVE
  Dipeptidyl peptidase-4 (DPP-4) is responsible for degradation of glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), the endogenous incretins that stimulate glucose-dependent insulin secretion. The objective was to evaluate preclinical profile of a novel DPP-4 inhibitor ZYDPLA1.
  
  
  METHODS
  In vitro inhibition potency and selectivity were assessed using recombinant enzymes and/or plasma. In vivo efficacy was determined in oral glucose tolerance test or mixed meal tolerance test in C57BL/6J mice, db/db mice and Zucker fatty rats. Pharmacokinetics/pharmacodynamics was studied in mice, rats, dogs, and non-human primates.
  
  
  RESULTS
  ZYDPLA1 is a potent, competitive and long acting inhibitor of DPP-4 (Ki 0.0027 μM; Koff 2.3 × 10(-4 ) s(-1) ). ZYDPLA1 was more than 7000-fold selective for recombinant DPP-4 relative to DPP-8 and DPP-9, and more than 60 000-fold selective relative to fibroblast activation protein (FAP) in vitro. DPP-4 inhibition was comparable across species. In vivo, oral ZYDPLA1 elevated circulating GLP-1 and insulin levels in mice and rats and showed dose-dependent anti-hyperglycemic effect. Anti-hyperglycemic effect was also observed in db/db mice and Zucker fatty rats. ZYDPLA1 showed low clearance, large volume of distribution, and a long half-life with excellent oral bioavailability in all species. It significantly inhibited plasma DPP-4 activity in mice and rats for more than 48 h, and for up to 168 h in dogs and non-human primates. Allometric scaling predicted a half-life in humans of 53 to 166 h.
  
  
  CONCLUSIONS
  ZYDPLA1 is a potent, selective, long-acting oral DPP-4 inhibitor with potential to become once-a-week therapy for treatment of type 2 diabetes mellitus.
authors.affiliation: Department of Pharmacology and Toxicology, Zydus Research Centre, Ahmedabad, India.
authors.forename: Mukul R
authors.initials: MR
authors.lastname: Jain
authors.affiliation: Department of Pharmacology and Toxicology, Zydus Research Centre, Ahmedabad, India.
authors.forename: Amit A
authors.initials: AA
authors.lastname: Joharapurkar
authors.affiliation: Department of Medicinal Chemistry, Zydus Research Centre, Ahmedabad, India.
authors.forename: Rajesh H
authors.initials: RH
authors.lastname: Bahekar
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Ahmedabad, India.
authors.forename: Harilal
authors.initials: H
authors.lastname: Patel
authors.affiliation: Department of Medicinal Chemistry, Zydus Research Centre, Ahmedabad, India.
authors.forename: Pradip
authors.initials: P
authors.lastname: Jadav
authors.affiliation: Department of Pharmacology and Toxicology, Zydus Research Centre, Ahmedabad, India.
authors.forename: Samadhan G
authors.initials: SG
authors.lastname: Kshirsagar
authors.affiliation: Department of Pharmacology and Toxicology, Zydus Research Centre, Ahmedabad, India.
authors.forename: Vishal J
authors.initials: VJ
authors.lastname: Patel
authors.affiliation: Department of Pharmacology and Toxicology, Zydus Research Centre, Ahmedabad, India.
authors.forename: Kartikkumar N
authors.initials: KN
authors.lastname: Patel
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Ahmedabad, India.
authors.forename: Vikram K
authors.initials: VK
authors.lastname: Ramanathan
authors.affiliation: Department of Pharmacology and Toxicology, Zydus Research Centre, Ahmedabad, India.|Department of Medicinal Chemistry, Zydus Research Centre, Ahmedabad, India.|Department of Drug Metabolism and Pharmacokinetics, Zydus Research Centre, Ahmedabad, India.
authors.forename: Pankaj R
authors.initials: PR
authors.lastname: Patel
authors.affiliation: Department of Medicinal Chemistry, Zydus Research Centre, Ahmedabad, India.
authors.forename: Ranjit C
authors.initials: RC
authors.lastname: Desai
mesh_terms: D000818:Animals; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011924:Rats, Zucker
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D052216:Glucagon-Like Peptide 1
keywords: dipeptidyl peptidase-4 inhibitor; incretins; long-acting; new drug; type 2 diabetes; 关键词：二肽基肽酶-4抑制剂，肠促胰岛素，长效，新药，2型糖尿病<