Discovery of a series of 2-(pyridinyl) pyrimidines as potent antagonists of GPR40

A series of 2-(pyridinyl)pyrimidines were identified as potent GPR40 antagonists. Despite significant challenges related to improving the combination of potency and lipophilicity within the series, the compounds were optimised to identify a suitable in vivo probe compound, which was confirmed to exhibit pharmacology consistent with GPR40 antagonism

Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4] oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors

Neutral DGAT1 inhibitors have been designed with comparable pre-clinical efficacy and PK/PD to those previously described for acidic inhibitors.</p

Optimisation of aqueous solubility in a series of G protein coupled receptor 119 (GPR119) agonists

Solubility improvements in a series of GPR119 agonists are achieved through reduction of lipophilicity together with hydrogen bond acceptor modulation.</p

The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1

<div><p>The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated <i>in vitro</i>. The acute glucose lowering effect was studied in lean wild-type and GPR120 <i>null</i> mice following oral or intravenous glucose tolerance tests. <i>In vitro</i>, in GPR120 overexpressing cells, both agonists signaled through Gα_q, Gα_s and the β-arrestin pathway. However, in mouse islets the signaling pathway was different since the agonists reduced cAMP production. The GPR120 agonists stimulated GLP-1 secretion both <i>in vitro</i> in STC-1 cells and <i>in vivo</i> following oral administration. <i>In vivo</i> GPR120 activation induced significant glucose lowering and increased insulin secretion after intravenous glucose administration in lean mice, while the agonists had no effect in GPR120 <i>null</i> mice. Exendin 9–39, a GLP-1 receptor antagonist, abolished the GPR120 induced effects on glucose and insulin following an intravenous glucose challenge. In conclusion, GLP-1 secretion is an important mechanism behind the acute glucose lowering effect following specific GPR120 activation.</p></div

Exendin 9–39 blocked the Metabolex-36 induced potentiation of insulin secretion in lean mice.

<p>Insulin levels following intravenous glucose challenge (<b>A</b>) and corresponding blood glucose (<b>C</b>), after administration of Metabolex-36, exendin 9–39 or a co-administration of both, with corresponding calculations of AIR (<b>B</b>) and glucose elimination (<b>D</b>). The IVGTT data are from two independent experiments with 6–7 mice per group. Data are presented as mean ± SEM.**p<0.01 and *p<0.05 versus vehicle control.</p

<i>In vitro</i> pharmacology of AZ13581837 and Metabolex-36.

<p><i>In vitro</i> pharmacology of AZ13581837 and Metabolex-36.</p

Structure of AZ13581837 and Metabolex-36 and specificity of the compounds for human and mouse GPR120 and human or mouse GPR40.

<p><b>A)</b> Chemical structure of AZ13581837 and <b>B)</b> Metabolex-36.<b>C)</b> Effect of AZ13581837 (squares) and Metabolex-36 (circles) on DMR response in CHO-hGPR120 (filled symbols) and CHO (open symbols). <b>D)</b> Activity in CHO-GPR40 cells for AZ13581837 (filled squares), Metabolex-36 (filled circles) and GW9508 (filled triangles). Activity in CHO-hGPR120 cells is shown as reference for AZ13581837 (open squares), Metabolex-36 (open circles) and GW9508 (open triangles). <b>E)</b> Cross species selectivity evaluated in CHO-mGPR120 cells using a DMR assay. Activity of AZ13581837 (squares) and Metabolex-36 (circles) on mouse GPR120 (filled symbols) compared to human GPR120 (open symbols). <b>F)</b> Cross species selectivity for GPR40 evaluated using a calcium mobilization assay. Effect of AZ13581837 (filled squares) and Metabolex-36 (filled circles) on mouse GPR40 with GW9508 (filled triangles) as reference. Activity in CHO-hGPR120 cells is shown as comparison for AZ13581837 (open squares) and Metabolex-36 (open circles). Data are shown as mean ± SEM run in duplicates or more and representative for two or more independent experiments.</p