Herein we describe the design and optimization

Herein, we describe the design and optimization of fused-ring phenyl propanoic acids as novel GPR40 agonists, leading to the discovery of compound 40a which exhibits excellent pharmacokinetic properties, improved hepatobiliary transporter inhibition, and significant glucose-lowering efficacy during an oral glucose tolerance test (OGTT) in SD rats as well as good druggability.
Results and discussion
Conclusion In summary, considering possible causes about the hepatotoxicity caused by TAK875 reported in literatures, a series of novel benzo-fused ring propanoic 1,3-PBIT dihydrobromide derivatives were designed in order to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety. Extensive structural modification and SAR study around these scaffolds led to several novel analogues with high in vitro GPR40 agonistic activities, exampled by 40a, 50a and 50d. Further pharmacokinetic profiles evaluation in SD rats demonstrated that compound 40a displayed a favorable PK profiles with the longest half-life and the highest plasm exposure. Compound 40a exhibited an obvious plasma glucose-lowering effect at an oral dose of 10 mg/kg at an OGTT in SD rats. Furthermore, compound 40a showed high selectivity over the relevant receptors GPR41, GPR120 and GPR119, which indicated a low off-target adverse activity. TAK875 was an inhibitor of multiple hepatobiliary transporters, which may result in cholestatic hepatotoxicity. Compared with TAK875, compound 40a demonstrated lower hepatobiliary transporter inhibition. In addition, compound 40a had promising druggability, such as low CYP450 inhibition, no genetic toxicity, and no hERG inhibition. In a two-week subacute toxicity study in rats, 40a was well tolerated. These attributes render compound 40a a suitable candidate for further evaluation.
Experimental section
Declaration of interest
Acknowledgements The work was supported by the National Natural Science Foundation of China (21402222) and the “Personalized Medicines – Molecular Signature-Based Drug Discovery and Development”, Strategic Priority Research Program of Chinese Academy of Sciences (XDA12040307), and the Youth Innovation Promotion Association of Chinese Academy of Sciences (2016262).
Introduction
Polyunsaturated fatty acids (PUFAs) and GPR40 (FFA1) receptor
Physiological role of GPR40 receptor
Role of GPR40 in neuropathological conditions
Concluding remarks It is an established fact that (PUFAs) are expressed abundantly in the nervous system, play a vital role in brain functioning, and serve as agonist for the GPR40 receptor. GPR40 currently appears to be a potential target in the management of several neuropathological conditions such as Alzheimer's disease, Parkinson's disease, neurogenesis, apoptosis, and inflammatory pain. Many studies have shown that PUFAs and GPR40 signaling contributes to the neurogensis, antinocieptive effects, anti-apoptotic effect, Ca2+ homeostasis in Alzheimer's disease and in the functioning of nigrostriatal pathways. However, there is a lack of clear data supporting its role in Alzheimer's disease and Parkinson's disease, therefore complementary studies are needed to fully clarify GPR40 functions and to determine in which condition(s) this receptor should be activated or blocked. Until now, no single study exists concerning the evaluation of the GPR40 role in the brain in genetically deficient mice. This emphasizes the need to evaluate its role in the brain by using KO mice models and to develop new pharmacological tools to ascertain the functional role of GPR40 in physiological and pathological conditions.
Acknowledgements We gratefully acknowledge funding from National 12th Five-year Plan “Major Scientific and Technological Special Project for Significant New Drugs Creation” project of “Novel G protein-coupled receptor targeted drug screening system and key technology research” (NO. 2012ZX09504001-001) and Program for New Century Excellent Talents in University (No. NCET-10-0817), which have supported aspects of our research covered in this review.