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- Title
Pharmacological characterization of ZYDPLA1, a novel long-acting dipeptidyl peptidase-4 inhibitor 一种新型的长效二肽基肽酶-4抑制剂ZYDPLA1的药理特性
- Authors
Jain, Mukul R.; Joharapurkar, Amit A.; Bahekar, Rajesh H.; Patel, Harilal; Jadav, Pradip; Kshirsagar, Samadhan G.; Patel, Vishal J.; Patel, Kartikkumar N.; Ramanathan, Vikram K.; Patel, Pankaj R.; Desai, Ranjit C.
- Abstract
Objective Dipeptidyl peptidase-4 ( DPP-4) is responsible for degradation of glucagon-like peptide 1 ( GLP-1) and gastric inhibitory polypeptide ( GIP), the endogenous incretins that stimulate glucose-dependent insulin secretion. The objective was to evaluate preclinical profile of a novel DPP-4 inhibitor ZYDPLA1. Methods In vitro inhibition potency and selectivity were assessed using recombinant enzymes and/or plasma. In vivo efficacy was determined in oral glucose tolerance test or mixed meal tolerance test in C57BL/ 6J mice, db/db mice and Zucker fatty rats. Pharmacokinetics/pharmacodynamics was studied in mice, rats, dogs, and non-human primates. Results ZYDPLA1 is a potent, competitive and long acting inhibitor of DPP-4 (Ki 0.0027 μM; Koff 2.3 × 10-4 s-1). ZYDPLA1 was more than 7000-fold selective for recombinant DPP-4 relative to DPP-8 and DPP-9, and more than 60 000-fold selective relative to fibroblast activation protein ( FAP) in vitro. DPP-4 inhibition was comparable across species. In vivo, oral ZYDPLA1 elevated circulating GLP-1 and insulin levels in mice and rats and showed dose-dependent anti-hyperglycemic effect. Anti-hyperglycemic effect was also observed in db/db mice and Zucker fatty rats. ZYDPLA1 showed low clearance, large volume of distribution, and a long half-life with excellent oral bioavailability in all species. It significantly inhibited plasma DPP-4 activity in mice and rats for more than 48 h, and for up to 168 h in dogs and non-human primates. Allometric scaling predicted a half-life in humans of 53 to 166 h. Conclusion ZYDPLA1 is a potent, selective, long-acting oral DPP-4 inhibitor with potential to become once-a-week therapy for treatment of type 2 diabetes mellitus.
- Subjects
CD26 antigen; INCRETINS; TYPE 2 diabetes treatment; GASTRIC inhibitory polypeptide; GLUCAGON-like peptide 1; LABORATORY rats; PHARMACOKINETICS
- Publication
Journal of Diabetes, 2015, Vol 7, Issue 5, p708
- ISSN
1753-0393
- Publication type
Article
- DOI
10.1111/1753-0407.12233