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. (17th December 2014)

• Record Type: Journal Article
• 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.
• Is Part Of: Journal of diabetes. Volume 7:Number 5(2015)
• Page Start: 708
• Page End: 717
• Publication Date: 2014-12-17
• Subjects: dipeptidyl peptidase‐4 inhibitor -- incretins -- long‐acting -- new drug -- type 2 diabetes; 关键词：二肽基肽酶‐4抑制剂，肠促胰岛素，长效，新药，2型糖尿病<; Diabetes -- Periodicals; 618.3646005
• DOI: 10.1111/1753-0407.12233
• Languages: English
• ISSNs: 1753-0393

Abstract

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 μ M; 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.