Naomi Rozentul1, Yosef Avrahami2, Moran Shubely1, Laura Levy1, Anna Munder1, Guy Cohen2, Erol Cerasi3, Shlomo Sasson4, Arie Gruzman5. 1. Division of Medicinal Chemistry, Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, 52900, Ramat-Gan, Israel. 2. Department of Pharmacology, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel. 3. The Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, 91120, Jerusalem, Israel. 4. Department of Pharmacology, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel. shlomo.sasson@mail.huji.ac.il. 5. Division of Medicinal Chemistry, Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, 52900, Ramat-Gan, Israel. gruzmaa@biu.ac.il.
Abstract
PURPOSE: A series of novel polycyclic aromatic compounds that augment the rate of glucose uptake in L6 myotubes and increase glucose-stimulated insulin secretion from beta-cells were synthesized. Designing these molecules, we have aimed at the two main pathogenic mechanisms of T2D, deficient insulin secretion and diminished glucose clearance. The ultimate purpose of this work was to create a novel antidiabetic drug candidate with bi-functional mode of action. METHODS: All presented compounds were synthesized, and characterized in house. INS-1E cells and L6 myoblasts were used for the experiments. The rate of glucose uptake, mechanism of action, level of insulin secretion and the druggability of the lead compound were studied. RESULTS: The lead compound (6-(1,3-dithiepan-2-yl)-2-phenylchromane), dose- and time-dependently at the low μM range increased the rate of glucose uptake in L6 myotubes and insulin secretion in INS-1E cells. The compound exerted its effects through the activation of the LKB1 (Liver Kinase B1)-AMPK pathway. In vitro metabolic parameters of this lead compound exhibited good druggability. CONCLUSIONS: We anticipate that bi-functionality (increased rate of glucose uptake and augmented insulin secretion) will allow the lead compound to be a starting point for the development of a novel class of antidiabetic drugs.
PURPOSE: A series of novel polycyclic aromatic compounds that augment the rate of glucose uptake in L6 myotubes and increase glucose-stimulated insulin secretion from beta-cells were synthesized. Designing these molecules, we have aimed at the two main pathogenic mechanisms of T2D, deficient insulin secretion and diminished glucose clearance. The ultimate purpose of this work was to create a novel antidiabetic drug candidate with bi-functional mode of action. METHODS: All presented compounds were synthesized, and characterized in house. INS-1E cells and L6 myoblasts were used for the experiments. The rate of glucose uptake, mechanism of action, level of insulin secretion and the druggability of the lead compound were studied. RESULTS: The lead compound (6-(1,3-dithiepan-2-yl)-2-phenylchromane), dose- and time-dependently at the low μM range increased the rate of glucose uptake in L6 myotubes and insulin secretion in INS-1E cells. The compound exerted its effects through the activation of the LKB1 (Liver Kinase B1)-AMPK pathway. In vitro metabolic parameters of this lead compound exhibited good druggability. CONCLUSIONS: We anticipate that bi-functionality (increased rate of glucose uptake and augmented insulin secretion) will allow the lead compound to be a starting point for the development of a novel class of antidiabetic drugs.