Discovery of AM-1638: A Potent and Orally Bioavailable GPR40/FFA1 Full Agonist

Abstract

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1. KEYWORDS: GPR40, full agonist, AM-1638, AMG 837, insulin secretagogue, FFA1 T ype II diabetics lose their ability to maintain glucose homeostasis due to defects in both insulin secretion and action.1 GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets.2 When activated by medium to long chain fatty acids, GPR40 elicits increased insulin secretion only in the presence of elevated glucose levels. 3This alluring mechanism to treat type II diabetes presents the potential of little or no risk of hypoglycemia and has been investigated by multiple groups, leading to the discovery of several clinical candidates.4−7 We previously described the discovery of AMG 837 (1), 8−10 a small molecule partial agonist of GPR40 that displays oral efficacy in a variety of rodent diabetic models without exhibiting hypoglycemia. Because of the robust antidiabetic activity and favorable pharmacokinetic properties, 1 was selected for clinical evaluation. Because the ability of partial agonist 1 to maintain glycemic control was being tested in a clinical setting, we became interested in interrogating GPR40 with full agonists. We hypothesized that a GPR40 full agonist should have a greater ability to induce insulin secretion and thus provide greater glycemic control. In this letter, we describe in detail the structure−activity relationship (SAR) studies that started from the GPR40 partial agonist 1 and culminate with the identification of GPR40 full agonist AM-1638 (21) and provide further evidence that GPR40 full agonists demonstrate superior efficacy over partial agonists when evaluated in vivo.To provide a greater dynamic range with which to assess improvements in intrinsic efficacy, we chose to reevaluate compounds previously synthesized toward discovery of partial agonist 1 in CHO cells transfected with lower levels of GPR40 expression plasmid [from 5.0 ( Figure 1A) to 0.05 μg ( Figure 1B)].9 Under the original 5.0 μg plasmid conditions, partial agonist 1 demonstrates 75% of the response (E max ) shown by the natural free fatty acid ligand docosahexaenoic acid (DHA) ( Figure 1A). In contrast, reducing the expression plasmid to 0.05 μg affords an assay with the appropriate dynamic range to distinguish GPR40 partial and full agonists. As depicted in Figure 1B, partial agonist 1 dis...

Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine

“…In the present study, the full FFAR1 agonists, AM-1638 (Brown et al. 2012) and AM-5262 (Wang et al. 2013), both caused a pronounced GLP-1 response, at least comparable to the response induced by intraluminal glucose (Fig.…”

“…2014) and full agonists, AM-1638 (Brown et al. 2011, 2012; Lin et al. 2012) and AM-5262 (Wang et al.…”

Small-Molecule Modulators of GPR40 (FFA1)

“…5 Interestingly, a structurally similar compound 10 (EC 50 ¼ 1.5 μM, E max ¼ 98%) displayed full agonist properties. 24 Separation of the enantiomers revealed that 11 retained full agonism (EC 50 ¼ 4.0 μM, E max ¼ 99%) while the corresponding enantiomer was a partial agonist (EC 50 ¼ 0.65 μM, E max ¼ 47%). Moving the ether linkage from the para to meta orientation along with further optimization of the biaryl rings and the β-chiral substituent provided agonist 12 (EC 50 ¼ 0.16 μM, E max ¼ 100%).…”

Design, synthesis and structure–activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

“…On the whole, the compound 13 series shared almost the same SAR with the compound 11 series (11 vs 13, 23 vs 24, 30 vs 31 and 32 vs 33). Interestingly, the introduction of gem-dimethyl group (14), however, showed a drastic loss of activity despite increased lipophilicity, suggesting that the limited space in the binding pocket around this area. Then, an initial optimization of the terminal phenyl with methyl group (15, 18, and 19) demonstrated that substitution is tolerated in all positions and preferred in the meta-substituent.…”

“…1), [9][10][11][12][13][14][15][16][17] and the compounds TAK-875, AMG-837 and LY2881835 were in clinical trials for treatment of T2DM. However, many of these agonists have relatively high molecular weight and lipophilicity (red mark in Fig.…”