GSK1292263 / GSK - LARVOL DELTA

Structural insights into the activation of G protein-coupled receptor 119 by the agonist GSK1292263 and ligands selectivity among novel cannabinoid receptors. (PubMed, Int J Biol Macromol) - "The homology-modeled structure of GPR18 suggests a compact binding pocket favoring bent or smaller ligands. Collectively, our findings provide a structural framework and mechanistic insights for the rational design of selective GPR119-targeted therapeutics for metabolic disorders."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • GPR55

Novel effects on lipids of GSK1292263, a GPR119 agonist, in type 2 diabetics (ADA 2012) - Presentation time: 6/9/2012 11:30:00 AM; P2,N=66; Article describes the safety, tolerability and PK of GSK1292263 and reported that 100-600mg/day for 14 days (n≈12 per arm) did not reduce AUCglucose (0-24h) as monotherapy or dosed with metformin or sitagliptin, but it increased circulating gut hormone levels, especially postprandial PYY; GSK1292263 also reduced significantly apoB(B100), with trends for a reduction of apoE and an elevation of apoA1

P2 data • Diabetes

Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: Results from two randomized studies (PLoS One) - P=NA, N=141; "GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263."

Clinical data • Dyslipidemia

DS-8500a, an orally available G protein-coupled receptor 119 agonist, upregulates glucagon-like peptide-1 and enhances glucose-dependent insulin secretion and improves glucose homeostasis in type 2 diabetic rats. (PubMed, J Pharmacol Exp Ther) - "In a repeat-dosing study, DS-8500a had statistically significant glucose-lowering effects at OGTT performed at the 1st day and after 2 weeks of treatment in neonatal streptozotocin-treated (nSTZ) rats, and the efficacy levels of DS-8500a in each test were greater than those of GSK1292263 or MBX-2982, which had been clinically tested previously as GPR119 agonists. Single dose of DS-8500a showed dose dependent glucose lowering effects at OGTT in ZF rats. In the repeat dosing study, DS-8500a had statistically significant glucose lowering effects at OGTT performed at the first day and after 2-weeks treatment in nSTZ rats, and the efficacy levels of DS-8500a in each test were greater than those of GSK1292263 or MBX-2982 which had been clinically tested GPR119 agonists."

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