| RESEARCH ARTICLE
|Year : 2012 | Volume
| Issue : 6 | Page : 759-764
Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model
Joseph A Davis1, Pucha S Kumar1, Shuchita Singh1, A Surender1, Subhasis Roy1, Vivek Khanna1, Sachin Sethi2, Chanchan Pal2, Lalima Sharma2, Biju Benjamin3, Shivani Mittra1, Jitendra Sattigeri2, Vinay S Bansal1
1 Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana, India
2 Department of Medicinal Chemistry, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana, India
3 Department of Metabolism and Pharmacokinetics, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana, India
Aim: 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.
Material and 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 IC 50 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.
Joseph A Davis
Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
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