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 RESEARCH ARTICLE
Year : 2012  |  Volume : 44  |  Issue : 6  |  Page : 759-764

Biological evaluation of RBx-0128, a potent and selective dipeptidyl peptidase-IV inhibitor in type 2 diabetes genetic model


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

Correspondence Address:
Joseph A Davis
Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7613.103298

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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.






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