Because AM had limited efficacy on rodent GPR

Because (AM-3189) had limited efficacy on rodent GPR40, we used two rodent models expressing human GPR40 to demonstrate efficacy of (AM-3189). First, we used human islet transplanted nude mice. In this model, endogenous pancreatic β-cells were ablated using streptozotocin, and mice were rescued to euglycemia using human islets transplanted under the kidney capsule. In these mice, (AM-8139) dosed at 1 and 10mg/kg po prior to a glucose challenge lowered glucose AUC levels (A). The glucose lowering effect was comparable to that of a 100μg/kg dose of GLP-1 (A). The efficacy of was also examined in human GPR40 knock-in mice. Again, (30mg/kgpo) lowered glucose levels during an OGTT (B andC). In summary, further optimization of beta-substituted carboxylic acids as GPR40 agonists led to the discovery of (AM-3189), a potent GPR40 agonist that has good pre-clinical pharmacokinetic properties and low CNS penetration. (AM-3189) represents a valuable tool in the exploration of the role that the GPR40 receptor may play in type II diabetes. Acknowledgments
Introduction Type 2 diabetes (T2DM) is a multifactorial disease and the most common form of diabetes mellitus [1]. The manifestation begins with elevated blood glucose levels due to failures in insulin secretion and/or insulin resistance [2], [3]. Central or visceral obesity plays the main role in the development of T2DM; it is well known that obesity leads to insulin resistance and it may represent a cardiovascular risk factor by ectopic lipid deposition and the increased release of free fatty acids into the circulation [4], [5]. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor; it has the highest expression level in adipocytes, and its activation regulates the GX15-070 metabolism and decreases blood lipids levels [3], [6], [7] through the increase in the expression of the target genes involved in glucose and lipids metabolism. The main target is GLUT4 (glucose transporter type 4), which is involved in glucose homeostasis by glucose uptake in the body, both muscle, and adipose tissue. Therefore, increased PPARγ expression in adipose tissue reduces the insulin resistance by increasing the GLUT4 expression [8], [9]. Therefore, PPARγ attractive therapeutic target as insulin sensitizer for the treatment of diabetes mellitus. On the other hand, an ineffective insulin secretion is the second reason why the blood glucose level is elevated [9]. Consequently, the induction of insulin output from β cells represents also a therapeutic strategy of choice. There are many insulin secretagogues such as sulfonylureas and meglitinides, which are widely used for the treatment of T2DM [10]. There are several agents that trigger glucose-stimulated insulin secretion, among which two new attractive drugs are the dipeptidyl peptidase-4 (DPP-4) inhibitors and the analogs of glucagon-like peptide-1 (GLP-1) [11]. Nevertheless, the insulin secretagogues have a high probability of producing hypoglycemia [12]. It has reported that both the free fatty acid receptor 1 and the G protein-coupled receptor (FFAR1 and GPR40, respectively) stimulate the insulin secretion [13]. The natural ligands of this receptor are free fatty acids (FFAs), which have pleiotropic effects on pancreatic β-cells promoting insulin secretion through GPR activation [14]. This attractive mechanism to treat T2DM presents very little or no risk of hypoglycemia because of the GPR40 has its effects on the second phase of insulin secretion (low secretion). Therefore, GPR40 contributes approximately to half of the full acute insulin secretory response and it has the capability to have a significant impact on multiple metabolic defects that contribute to the disease [15], [16], [17]. An instance of these agents is TAK-875 (fasiglifam), an orally available GPR40 agonist that enhances glucose-dependent insulin secretion with efficacy and safety in a phase III trial [18], [19].