In summary we have designed
In summary, we have designed and optimized a new series of 1,4-dioxycyclohexane GPR119 agonists. SAR studies led to the discovery of the preferred molecule that has potent and efficacious GPR119 activity across species. This lead compound exhibited an excellent ADME and safety profile, and demonstrated robust regulatory effects on glycemic parameters in the acute and chronic diabetic or non-diabetic rodent models. Subsequent investigation of and further development of this novel series will be disclosed elsewhere.
Introduction The prevalence of cardiovascular disease (CVD) is increasing rapidly and is now a leading cause of death globally (Califf et al., 2010). Cardiovascular pathologies are the leading cause of death in type 2 diabetes, with those with this condition being twice as likely to suffer a fatal myocardial infarction compared to those without type 2 diabetes (De Groote et al, 2004, Donahoe et al, 2007, Haffner et al, 1998, Miettinen et al, 1998). The healthy adult heart relies predominantly on fatty acids for energy production (Kolwicz and Tian, 2009), with aberrations in myocardial fatty Bisindolylmaleimide IV and glucose metabolism contributing to cardiac energetic stress and impaired function including contractile dysfunction and pathological cardiac remodelling and hypertrophy (Ardehali et al, 2012, Jaswal et al, 2011, Yan et al, 2009, Young et al, 2002). G-protein coupled receptor 119 (GPR119) agonists are being developed primarily for the treatment of type 2 diabetes. Endogenous activation of GPR119 is largely via fatty acid derivatives (Chu et al, 2010, Kogure et al, 2011, Lan et al, 2009, Ning et al, 2008, Overton et al, 2006, Soga et al, 2005), with its activation having beneficial roles in regulating appetite and parameters of glycaemia including pancreatic beta cell mass, insulin and glucagon-like peptide-1 (GLP-1) secretion (Chu et al, 2007, Chu et al, 2008, Gao et al, 2011a, Gao et al, 2011b, Lauffer et al, 2009, Overton et al, 2006). A recent study has also suggested GPR119 as a possible therapeutic target for CVD though modulating lipidaemia and cholesterol metabolism (Cornall et al, 2013a, Hu et al, 2014). To date no research has investigated the effect GPR119 agonism in the heart. Accordingly, we aimed to investigate the effect of GPR119 activation in regulating cardiac cell nutrient metabolism and hypertrophy in the presence and absence of a high fat environment in vitro.
Materials and methods
Discussion GPR119 agonists are postulated as a treatment for type 2 diabetes, with some studies also suggesting positive effects on body weight regulation and cardiovascular health (Cornall et al, 2013a, Nunez et al, 2014, Overton et al, 2006). However, the long term utility of GPR119 agonists in regulating metabolic health is still unknown. Given that CVD is the leading cause of morbidity in individuals with diabetes (De Groote et al, 2004, Donahoe et al, 2007, Haffner et al, 1998, Miettinen et al, 1998), understanding the effects of GPR119 agonists in the heart is essential. This study is the first to investigate the specific effects of GPR119 agonists in cardiac muscle cells on metabolic and hypertrophic processes in metabolically normal and dysregulated cells. The salient outcomes of this study show that the GPR119 agonist, PSN632408, decreases total metabolic activity in H9c2 cardiac myoblasts in conditions of both high and low palmitate, and that GPR119 signals through differing metabolic pathways to elicit these effects in the presence and absence of palmitate-induced metabolic dysregulation. While this study is limited to data generated from in vitro analysis, it highlights a paucity in the current literature regarding our understanding of the cardiac functions of GPR119 and provides an important basis for further work. Of particular importance, direct activation of GPR119 in cardiac muscle cells decreased the overall mitochondrial metabolic capacity of H9c2 cells in both normal cells and those that had been exposed to palmitate to induce metabolic dysfunction. In our hands this was evidenced by increased lipid accumulation and hypertrophic remodelling of these cells subsequent to palmitate treatment. This finding suggests that in both healthy individuals and those with obesity and/or type 2 diabetes, cardiac muscle mitochondrial function will be impaired by activating GPR119. Interestingly however, overall ATP production was increased in response to PSN632408 in conditions of basal fatty acid exposure. In view of the current reduction in mitochondrial metabolic capacity and reduction in mRNA expression of AMPKα, PPARα and NFATc3, it is appealing to speculate that the increase in ATP is a result of up-regulation of glycolytic metabolism. Chronically, over-reliance on glycolytic metabolism, which is uncoupled from mitochondrial oxidative glucose metabolism, contributes to multiple cardiac defects and reduced cardiac efficiency (Kolwicz, Tian, 2009, Lopaschuk et al, 2010, Young et al, 2002). Unlike the data regarding mitochondrial metabolism, there was no difference in ATP production when GPR119 was activated in the presence of palmitate. It is well established that people with type 2 diabetes are at a significantly increased risk of adverse cardiovascular events leading to death (De Groote et al, 2004, Donahoe et al, 2007, Haffner et al, 1998, Miettinen et al, 1998). Thus it would be hoped that any potential anti-diabetic agent would improve cardiac muscle metabolism and function to reduce this risk. However the finding that GPR119 activation in heart cells reduces cardiac muscle mitochondrial metabolism is consistent with the reduction that we have previously seen in skeletal muscle cells (Cornall et al., 2013b). Taken together this suggests that activating GPR119 in muscle, either cardiac or skeletal muscle, is not likely to prove beneficial.