Previous studies have suggested that

Previous studies have suggested that GPR40 protects from bone loss via inhibition of osteoclasts. Wittrant et al. used GPR40 knock-out mice and primary osteoclasts to investigate the role of GPR40 on bone remodelling. Their results in primary osteoclast cultures and the RAW264.7 cell line showed that GPR40 significantly inhibited osteoclastic differentiation by modulating Rank/OPG. Furthermore, they performed in vivo experiments to investigate whether GPR40 protects from bone loss and suggested that GW9508 gavage protected ovariectomized mice from bone loss. However, gavage of the drug may affect the entire body endocrinology, which could indirectly change bone mass or density. To avoid these problems, we performed marrow cavity injection of increasing concentrations of GW9508 into the femur of ovariectomized (OVX) mice to further dig the direct effect of GPR40 on bone metabolism.
Conflict of interest
Acknowledgment This work was supported by the Ministry of Science and Technology of China (2011CB964703), National High Technology Research and Development Program 863 (2012AA020502) and National Natural Science Foundation of China (81472043), and and the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT13051). No benefits in any form have been or will be received from a commercial party directly or indirectly by the authors of this manuscript.
The G-protein coupled receptor GPR40 (also known as free fatty Doxorubicin receptor 1, FFAR1) is highly expressed in human and rodent pancreatic islets and is activated by medium and long-chain free fatty acids (e.g., linoleic and palmitic acids) resulting in stimulation of downstream signaling pathways which activate protein kinase C (PKC) and elevate intracellular [Ca]., Since both activation of PKC and increasing intracellular [Ca] play a key role in insulin exocytosis in pancreatic β-cells, GPR40 may serve as a signaling mechanism through which free fatty acids directly affect insulin secretion. Treatment of MIN6 pancreatic β-cells with small interfering RNA (siRNA) specific for GPR40 prevents fatty acid stimulation of insulin secretion. This study further supported that GPR40 may serve as an attractive target to mediate insulin secretion. Furthermore, agents that serve as GPR40 agonists may be useful for the treatment of type-2 diabetes., , , In the literature, different classes of GPR40 agonists are reported (beyond the fatty acids) as shown in . These include aminophenyl propionic acid derivative GW9508 (, pEC 7.1, GlaxoSmithcline),, , 4-alkoxy phenyl propionic acid derivative (EC 0.3μM, Johnson and Johnson), bicyclic compound (EC 0.1–100nM, Merck), 4,5-diphenyl-pyrimidinylamino substituted carboxylic acid (104% activation at 100μM, Sanofi-Aventis), phenylamino-benzoxazole substituted carboxylic acid (111% activation at 100μM, Sanofi-Aventis), oxadiazolidinedione compound (EC 0.26μM, Astellas Pharma), bicyclic carboxylic acid derivative (EC<0.1μM, Amgen Inc.), thiazolidinedione (pEC 5.1, Heptahelix AB), conformationally constrained 3-(4-hydroxy-phenyl)-substituted propanoic acid (EC 0.01μM, Amgen Inc.), cyclopropane carboxylic acid compound (119% activation at 100μM, Takeda Pharmaceuticals) and phenylpropanoic acid derivative (EC 19nM, Takeda Pharmaceuticals). Besides these reports, Tikhonoca et al. have recently identified different new scaffolds active at FFAR1 as full agonists, partial agonists or pure antagonists by virtual screening based on two-dimensional (2D) similarity, three-dimensional (3D) pharmacophore searches and docking studies using structure of known agonists., Most of these compounds possess terminal carboxylic acid group with a tether linking to an aromatic nucleus. This letter describes our research efforts towards identification of diacylphloroglucinols as a new series of GPR40 agonists. Acyl phloroglucinol compounds widely occur in nature in Myrtaceae family and are reported to possess wide range of biological activities viz. antimicrobial, antileishmanial, antimalarial, cancer chemopreventive, antifouling, anti-HIV and plant growth regulatory activity., , Apart from these reports, this class of compounds are also reported to possess antidiabetic activities viz. macrocarpals isolated from inhibit aldose reductase which is the target enzyme for the control of diabetic complications such as cataracts, retinopathy, neuropathy and nephropathy; achyrofuran has been isolated from by bioactivity-guided fractionation using the db/db mouse model for type-2 diabetes and it significantly lowered blood glucose levels in this model when administered orally at 20mg/kg/day; and phlorotannins, such as eckols isolated from exhibited inhibitory activity on glycation and R-amylase and thus possess the potential for the effective treatment of diabetic complications. But this class of compounds have never been evaluated for their GPR40 agonistic potential.