Pharmacological Evaluation of SKL-18287, a New Long-Acting Glucagon-Like Peptide-1 Receptor Agonist with Enhanced Aggregation Propensity, in Rodent Models

Very recently, we have reported a new glucagon-like peptide-1 (GLP-1) receptor agonist, SKL-18287, (EC50: 1.2 and 0.13 nM for mouse and human, respectively) with extended in vivo half-life (T1/2: 5.8 h in rats), which is a medium-sized oligopeptide comprised of only natural l-amino acids. SKL-18287 is believed to exist in oligomeric form in vivo with a molecular weight of approximately 40,000 Da, which accounts for its extended in vivo half-life. This unique property may set SKL-18287 apart from other marketed GLP-1-based drugs. In this study, we report the pharmacological effects of SKL-18287 on type 2 diabetes mellitus (T2DM) and gastric emptying (GE) in several animal models. In intraperitoneal glucose tolerance tests, SKL-18287 lowered blood glucose level in a dose-dependent manner. Significant differences were observed between the control- and SKL-18287-treated groups at 0–1 h after the 1st and 2nd glucose loading. SKL-18287 glucose-lowering effect was virtually the same for both glucose loadings. In non-obese type 2 diabetic Goto-Kakizaki (GK) rats, SKL-18287, given a range of 6–12 nmol/kg/daily, produced a robust beneficial effect on glycohemoglobin (GHb). As for liraglutide, the 8 nmol/kg/daily dose failed to produce any significant effect on GHb. SKL-18287 had more potent therapeutic effects than liraglutide in GK rats, while it had marginal effect on GE. These results suggested that SKL-18287 was more pancreas-selective than liraglutide and would mitigate gastrointestinal adverse effects such as nausea and vomiting. SKL-18287 might be useful for non-obese patients with T2DM.