br Results and discussion br Conclusions TZDs represent a we

Results and discussion
Conclusions TZDs represent a well-studied group of antidiabetic agents. Based on previous observations of the ability of some TZDs to activate FFAR1, we designed five scaffolds consisting of the TZD head, a linker, and a carefully selected privileged structure. For the present study, we decided to explore three of these scaffolds and nineteen compounds were synthesized. Nine of the prepared compounds showed acceptable activity on both receptors with series 5, the benzimidazole-based series, being the most promising. Our docking study indicated that polar interactions with the H bonding triad of PPARγ or FFAR1 is more important for receptor activation than hydrophobic interactions. It should be emphasized that the main objective of this work was not to obtain a highly potent agonist on PPARγ or FFAR1, but to design a lead ONX0914 with a balanced activity on both targets. The benzimidazole series 5, followed by the biphenyl series 1, were proved to be the most suitable scaffolds for this purpose. They provide a privileged structure with suitable shape and size for further fine-tuning of the activity on both receptors. Future studies in our laboratory will aim to optimize these lead compounds as well as to explore the remaining scaffolds, 3 and 4. We hope that these efforts could lead to the discovery of a dual acting antidiabetic agent to replace some of the currently used drug combinations.
Experimental
Acknowledgment This study was entirely funded by the Science and Technology Development Fund (STDF), Egypt, Grant #4244, awarded to the Principal Investigator Dr. Mohamed A. Helal. The authors would like to thank Dr. Safwat A. Ahmad, Pharmacognosy Department, Faculty of Pharmacy, Suez Canal University, for providing access to some necessary laboratory equipment. The authors would also like to thank Dr. Mohamed Saleh Elgawish, Graduate School of Biomedical Sciences, Course of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan, for performing mass and specific rotation measurements.
Introduction GLP-1 mimetics, such as exenatide and liraglutide have over the last years become widely used in the treatment of type 2 diabetes. The success of GLP-1 mimetics is based on the fact that they function not only as incretins, i.e. compounds which stimulate insulin secretion in a glucose dependent manner, but that they also suppress glucagon secretion, delay gastric emptying, decrease appetite and promote β-cell survival [1], [2]. However GLP-1 itself is just one out of a handful of gut hormones with similar beneficial metabolic properties, which all are released in response to food ingestion from closely related enteroendocrine cells scattered along the small and large intestine [3], [4]. The co-released gut hormones act in symphony and in several cases even synergistically [5]. Thus, it could be tempting to try to develop compounds, which stimulate the secretion of the powerful mixture of endogenous gut hormones [6], [7]; compounds, which may not even enter the body as such, but act locally in the gut [6]. Metabolites of dietary triglycerides, i.e. free fatty acids (FFA) and 2-monoacyl glycerol (2-MAG) are among the most efficacious gut hormone secretagogues [8], [9] conceivably acting through the G protein-coupled receptors GPR40 [10], [11], [12], [13], [14] and GPR119 [9], [15], respectively. Since these receptors are highly expressed on β-cells of the endocrine pancreas, they rapidly became high priority drug discovery targets for new anti-diabetes agents. A number of GPR119 agonists reached phase II [9], [16], but, although the compounds stimulated GLP-1 and insulin secretion in preclinical models they apparently did not deliver the required clinical efficacy perhaps due to their ability to also stimulate the secretion of the counter regulatory hormone glucagon [9]. GPR40 was originally deorphanized as a receptor for medium to long chain fatty acids being almost exclusively expressed in the β-cells and potentially responsible for the glucose-dependent stimulation of insulin secretion by long chain fatty acids (LCFA) [10], [11], [12], [17]. However, the notion that GPR40 potentially was involved in lipotoxicity made it unclear whether you wanted agonists or antagonists and whether GPR40 would at all be a good drug target [17], [18]. However, transgenic overexpression of GPR40 and administration of selective agonists later demonstrated that GPR40 activation augments insulin secretion and improves glucose tolerance and that GPR40 may even protect islets from the toxic effect of fatty acids [19], [20], [21]. Importantly, GPR40 was shown to be highly expressed and enriched also on enteroendocrine cells and to mediate GLP-1 and GIP secretion [22], [23].