Pharmacological characterization of ZYDPLA1, a novel long-acting dipeptidyl peptidase-4 inhibitor.

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.

Therapeutic potential of coagonists of glucagon and GLP-1.

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduces body weight without inducing hyperglycemia. In addition, coagonists have demonstrated lipid lowering property, which was independent of their anorectic effect. Similarly, GLP-1 modulates cardiovascular function which is favorable for treatment of myocardial injury, cardiac dysfunction, cardiac arrhythmias, endothelial dysfunction, and blood pressure, while glucagon has a positive impact on heart rate, cardiac output, ventricular contraction and enhances cardiac performance in animals and humans. Hence, researchers focused on combining these attributes of GLP-1 and glucagon in a single molecule, which was termed as a coagonist. Oxyntomodulin is the naturally occurring coagonist of GLP-1 and glucagon. This review focusses on the coagonists under clinical development discussing activities affecting cardiovascular functions, lipid modulation, direct effect on cardiac functions or other related functions. A comparative analysis of the in vitro and in vivo properties of GLP-1, glucagon and the coagonists is also carried out. This review discusses potential of GLP-1 and glucagon coagonists in treatment of cardiovascular and hemodynamic diseases with attention to GLP-1 or glucagon receptor specific properties as well as the interaction between other therapies.