RBx-0597, a potent, selective and slow-binding inhibitor of dipeptidyl peptidase-IV for the treatment of type 2 diabetes

• Published in: European journal of pharmacology Vol. 652; no. 1; pp. 157 - 163
• Main Authors: Singh, Shuchita, Sethi, Sachin, Khanna, Vivek, Benjamin, Biju, Kant, Rajiv, Sattigeri, Jitendra, Bansal, Vinay S, Bhatnagar, Pradip Kumar, Davis, Joseph Alex
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 10.02.2011; Elsevier
• Subjects: Animals; Anti-diabetic effect; bioavailability; Biological and medical sciences; blood glucose; Blood Glucose - analysis; Blood Glucose - metabolism; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes. Impaired glucose tolerance; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl peptidase-IV; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Drug; drug therapy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glucagon-like peptide-1; glucose; Glucose Tolerance Test; glycemic effect; humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; inhibitory concentration 50; insulin; Insulin - blood; Insulin - therapeutic use; Kinetics; Male; Medical sciences; Mice; Mice, Obese; noninsulin-dependent diabetes mellitus; Oral glucose tolerance test; pharmacokinetics; Pharmacology. Drug treatments; proteinases; Rats; Rats, Wistar; Type 2 diabetes mellitus; Oral glucose tolerance test; Glucagon-like peptide-1; Type 2 diabetes mellitus; Anti-diabetic effect; Dipeptidyl peptidase-IV; Endocrinopathy; Type 2 diabetes; Dipeptidyl-peptidase IV; Enzyme; Oral administration; Metabolic diseases; Glucose tolerance test; Glucagon like peptide 1; Peptidases; Hypoglycemic agent; Gastrointestinal hormone; Treatment; Hydrolases; Inhibitor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2010.06.001

Dipeptidyl peptidase IV (DPP-IV) inhibiton is a well recognized approach to treat Type 2 diabetes. RBx-0597 is a novel DPP-IV inhibitor discovered in our laboratory. The aim of the present study was to characterize the pharmacological profiles of RBx-0597 in vitro and in vivo as an anti-diabetic agent. RBx-0597 inhibited human, mouse and rat plasma DPP-IV activity with IC 50 values of 32, 31 and 39 nM respectively. RBx-0597 exhibited significant selectivity over dipeptidyl peptidase8 (DPP-8), dipeptidyl peptidase9 (DPP-9) (150–300 fold) and other proline-specific proteases (> 200–2000 fold). Kinetic analysis revealed that RBx-0597 is a competitive and slow binding DPP-IV inhibitor. In ob/ob mice, RBx-0597 (10 mg/kg) inhibited plasma DPP-IV activity upto 50% 8 h post-dose and showed a dose-dependent glucose excursion. RBx-0597 (10 mg/kg) showed a significant glucose lowering effect (∼ 25% AUC of △ blood glucose) which was sustained till 12 h, significantly increased the active glucagon-like peptide-1(GLP-1) and insulin levels. It showed a favourable pharmacokinetic profile (plasma clearance:174 ml/min/kg; C max 292 ng/ml; T 1/2 0.28 h; T max 0.75 h and V ss 4.13 L/kg) in Wistar rats with the oral bioavailability ( F oral) of 65%. In summary, the present studies indicate that RBx-0597 is a novel DPP-IV inhibitor with anti-hyperglycemic effect and a promising candidate for further development as a drug for the treatment of type 2 diabetes.