title: Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model.
abstract: OBJECTIVE
  Dipeptidyl peptidase IV (DPP-IV) inhibition to modulate the incretin effect is a proven strategy to treat type 2 diabetes mellitus. The present study describes the pharmacological profile of a novel DPP-IV inhibitor RBx-0128, as an antidiabetic agent.
  
  
  METHODS
  DPP-IV assay was carried out to evaluate in vitro potency of RBx-0128 using human, mouse, and rat plasma as an enzyme source. Selectivity was assessed with various serine proteases. In vivo efficacy was assessed in ob/ob mice. The pharmacokinetic (PK) profile was performed in Wistar rats.
  
  
  RESULTS
  RBx-0128 inhibited human, mouse, and rat plasma DPP-IV activity with IC50 values of 10.6, 18.1, and 56.0 nM respectively, selective over various serine proteases (900-9000-fold). The inhibition was reversible and competitive in nature. In ob/ob mice, RBx-0128 significantly (P<0.05) inhibited plasma DPP-IV and stimulated GLP-1 and insulin at 10 mg/kg. In the oral glucose tolerance test (OGTT), glucose lowering effect was better than sitagliptin (23 vs. 17%) at 10 mg/kg. The effect was sustained till 8 hours (30-35%) at 10 mg/kg with favorable PK profile (plasma clearance: 39.3 ml/min/kg; Cmax 790 ng/ml; t1/2 1.6 hours; tmax 4.8 hours, Vss 3.24 l/kg and Foral 55%) in Wistar rats.
  
  
  CONCLUSIONS
  The present study showed that RBx-0128 is a novel, DPP-IV inhibitor with an antihyperglycemic effect. It can be a promising candidate for the treatment of type 2 diabetes mellitus.
authors.affiliation: Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana, India.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Davis
authors.forename: Pucha S
authors.initials: PS
authors.lastname: Kumar
authors.forename: Shuchita
authors.initials: S
authors.lastname: Singh
authors.forename: A
authors.initials: A
authors.lastname: Surender
authors.forename: Subhasis
authors.initials: S
authors.lastname: Roy
authors.forename: Vivek
authors.initials: V
authors.lastname: Khanna
authors.forename: Sachin
authors.initials: S
authors.lastname: Sethi
authors.forename: Chanchan
authors.initials: C
authors.lastname: Pal
authors.forename: Lalima
authors.initials: L
authors.lastname: Sharma
authors.forename: Biju
authors.initials: B
authors.lastname: Benjamin
authors.forename: Shivani
authors.initials: S
authors.lastname: Mittra
authors.forename: Jitendra
authors.initials: J
authors.lastname: Sattigeri
authors.forename: Vinay S
authors.initials: VS
authors.lastname: Bansal
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D017208:Rats, Wistar
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4