Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of JNJ-38431055, a Novel GPR119 Receptor Agonist and Potential Antidiabetes Agent, in Healthy Male Subjects

Abstract

The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.

Discovery and characterization of novel smallmolecule agonists of G protein-coupled receptor 119

“…These GPR119 agonists induced GSIS from pancreatic β-cells only under high-glucose conditions and displayed in vivo activity. JNJ-38431055 from Johnson & Johnson progressed to clinical trials with positive results but was terminated shortly afterwards, presumably because of subpar performance in the trials [31] . GSK-1292263 by GlaxoSmithKline has also completed Phase 2 clinical trials and was reported to be well-tolerated in preliminary findings [32] .…”

Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice

“…Currently no specific GPR119 antagonists are commercially available however studies have shown that GLP-1 receptor antagonist exendin (9-39) reduces glucose lowering ability of AR-231453 in mice (Chu et al, 2008;Flock et al, 2011). Clinical trials with GPR119 agonists namely JNJ-38431055 have shown therapeutic potential that may be augmented with the administered DPP-IV inhibitor (Katz et al, 2011(Katz et al, , 2012.…”

GPR119 regulates genetic markers of fatty acid oxidation in cultured skeletal muscle myotubes

“…GPR119 agonism increases the release of incretin hormones and insulin from enteroendocrine and pancreatic beta cells which may underlie these beneficial effects (Chu et al, 2007;Gao et al, 2011;Lauffer et al, 2009). As a result of these advantageous effects GPR119 agonists have recently progressed to clinical trials (Katz et al, 2011).…”