| RBx-0597, a potent, selective and slow-binding inhibitor of dipeptidyl peptidase-IV for the treatment of type 2 diabetes. | |
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MedLine Citation:
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PMID: 20540938 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 39nM 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 (10mg/kg) inhibited plasma DPP-IV activity upto 50% 8h post-dose and showed a dose-dependent glucose excursion. RBx-0597 (10mg/kg) showed a significant glucose lowering effect (∼25% AUC of △ blood glucose) which was sustained till 12h, significantly increased the active glucagon-like peptide-1(GLP-1) and insulin levels. It showed a favourable pharmacokinetic profile (plasma clearance:174ml/min/kg; C(max) 292ng/ml; T(1/2) 0.28h; T(max) 0.75h and V(ss) 4.13L/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. |
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Authors:
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Shuchita Singh; Subhasis Roy; Sachin Sethi; Biju Benjamin; Sindhuja Sundaram; Vivek Khanna; Sachin R Kandalkar; Chanchal Pal; Rajiv Kant; Ashok Kumar Patra; Geetavani Rayasam; Shivani Mittra; Kulvinder Singh Saini; Jyoti Paliwal; Anita Chugh; Shahadat Ahmed; Jitendra Sattigeri; Ian Cliff; Abhijit Ray; Vinay S Bansal; Pradip Kumar Bhatnagar; Joseph Alex Davis |
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Publication Detail:
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Type: Journal Article Date: 2010-06-09 |
Journal Detail:
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Title: European journal of pharmacology Volume: 652 ISSN: 1879-0712 ISO Abbreviation: Eur. J. Pharmacol. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-03 Completed Date: 2011-04-18 Revised Date: 2011-04-25 |
Medline Journal Info:
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Nlm Unique ID: 1254354 Medline TA: Eur J Pharmacol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 157-63 Citation Subset: IM |
Copyright Information:
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2010 Elsevier B.V. All rights reserved. |
Affiliation:
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Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana-122001, India. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood Glucose / analysis, metabolism Diabetes Mellitus, Type 2 / blood, drug therapy*, metabolism, pathology Dipeptidyl Peptidase 4 / blood, metabolism* Dipeptidyl-Peptidase IV Inhibitors / administration & dosage, pharmacology, therapeutic use* Disease Models, Animal Dose-Response Relationship, Drug Female Glucose Tolerance Test Hypoglycemic Agents / administration & dosage, pharmacology, therapeutic use* Insulin / blood, therapeutic use Kinetics Male Mice Mice, Obese Rats Rats, Wistar |
| Chemical | |
Reg. No./Substance:
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0/Blood Glucose; 0/Dipeptidyl-Peptidase IV Inhibitors; 0/Hypoglycemic Agents; 11061-68-0/Insulin; EC 3.4.14.5/Dipeptidyl Peptidase 4 |
| Comments/Corrections | |
Erratum In:
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Eur J Pharmacol. 2011 Mar 25;655(1-3):121 Note: multiple author names added |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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