For our test subjects we used established high fat
For our test subjects, we used established high fat diet–induced obese (eDIO) male mices T2DM models. The establishment of eDIO mice was accomplished with a 60% high fat diet ad libitum over a 14 week period (initiated at 6 weeks of age). Compared with regularly-dieted mice, the eDIO ones weigh significantly heavier (51 ± 0.9 vs. 25 ± 0.7 g; n = 5; < 0.05) and show glucose intolerance manifestation (Random blood glucose levels: 131 ± 0.9 vs. 87 ± 0.8 mg/dL; n = 5; < 0.05). Our test compounds, rosiglitazone, and the vehicle (DMSO, as a negative control) were intravenousely dosed through tail at 10 mg/kg/day for 14 days run. As depicted in , both indole-based compounds ( and ) presented much greater euglycemic capabilities than series compounds ( and ). This could be attributed to the much greater transactivation of the PPAR-γ receptor furnished by these fused-ring derivatives. It is worth noting that SAG showed a 6-fold reduction in blood glucose levels compared that of rosiglitazone. Interestingly, both and offered statistically significant reduction of 5.5- and 3.5-fold, respectively, relative to rosiglitazone, in the TG plasma levels. These augmented potencies might be ascribed to better pharmacokinetics profiles when compared to their respective unsubstituted series members ( and ). The above results also reflect the excellent anti-hyperglycemic/hyperlipidemic profiles of that came in accordance with the activities. Seeking for better credibility, we further investigate the dual-agonistic activity of our promising candidate () against both the native insulinagogue Glimepride, a sulphonylurea derivative, and the insulin sensitizer Rosiglitazone, a PPAR-γ agonist. Throughout this second assay, we adopted the same previous (eDIO) mice model where we have evaluated the hypoglycemic/hypolipidemic activities via assessing the random blood glucose and plasma TG levels, as well as, the mice body weights. As depicted in , lower blood glucose level is noticed with compared to Rosiglitazone and Glimepride, individually or in combination. Notably, the body weight reductions, in case of , was higher than that of Rosiglitazone but lower than the Glipepiride's. Concerning plasma TG, satisfactory reduced levels were detected for our candidate (). The overall results, form the two investigations, suggest that is a promising lead compound that could pave the way for further development of the first clinically useful PPAR-γ/FFAR1 dual agonists. In our continued quest for dual PPAR-γ/FFAR1 agonists, we herein introduced the benzhydrol- and indole-tailed thiazolidindiones chemotypes. Both series were rationally designed as better successors of our recently published biphenyl-, phenyloxybenzyl-, and benzimidazoles. Down to low micromolar potencies, compounds , , and exhibited moderate and balanced dual activities on both targets. Among them, Compound showed better anti-hyperglycemic and anti-hyperlipidemic activities in fat-fed animal models compared to rosiglitazone. This was rationally explained using our molecular docking simulation studies. Those qualities made compound a promising candidate for more advanced preclinical studies. Acknowledgments This research was entirely supported by the Science and Technology Development Fund (STDF), Egypt (project grant # 4244) awarded to the Principal Investigator Dr. Mohamed A. Helal. The authors are grateful to Prof. Dr. Soad H. Abou El-Ela, Dean of the Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, El-Arish, Egypt; for providing the access to the HPLC/diiodo array instrumentation used in the analysis of our compounds’ purity. The authors would also like to thank Dr. Mohamed S. Elgawish, Graduate School of Biomedical Sciences, Course of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan, for performing the mass measurements.