Design, Synthesis, and Biological Activity of Potent and Orally Available G Protein-Coupled Receptor 40 Agonists

Abstract

G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic β-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC(50) = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC(50) = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.

Identification and Pharmacological Characterization of Multiple Allosteric Binding Sites on the Free Fatty Acid 1 Receptor

“…Several synthetic agonists for the FFA1 receptor have recently been identified (Christiansen et al, 2008;Bharate et al, 2009;Hara et al, 2009;Zhou et al, 2010;Lin et al, 2011;Sasaki et al, 2011;Tsujihata et al, 2011;Walsh et al, 2011). Antagonists have also been described Humphries et al, 2009;Hu et al, 2010).…”

“…A number of potent GPR40 synthetic ligands have been reported (Christiansen et al, 2008;Sasaki et al, 2011;Walsh et al, 2011), including two agonists that have entered the clinic, [(3S)-6-({2Ј,6Ј-dimethyl-4Ј-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate (TAK-875) (Araki et al, 2012;Naik et al, 2012) and (S)-3(-4-((4Ј-(trifluoromethyl)-[1,1Ј-biphenyl]-3-yl)methoxy) phenyl) hex-4-ynoic acid (AMG 837) (Lin et al, 2011).…”

Novel Pentadecenyl Tetrazole Enhances Susceptibility of Methicillin-Resistant Staphylococcus aureus Biofilms to Gentamicin

“…The data described herein suggest that further lead optimization is warranted. Recently, researchers at Takeda reported the identification of a potent development candidate for type 2 diabetes inspired by docosahexaenoic acid (26), which consists of a linear carbon chain structurally comparable to palmitoleic acid. This example offers compelling evidence that the optimization of SEQ-914 or other biologically active fatty acids into more potent and druglike development candidates is feasible.…”

Small-Molecule Modulators of GPR40 (FFA1)

“…Optimization led to potent agonist 2 (EC 50 ¼ 5.7 nM), a ligand with moderate bioavailability (F ¼ 21%) and high clearance (Cl ¼ 900 mL/h/kg) in rats, resulting in low exposure (AUC po ¼ 0.25 μgÁh/mL). 7 Oxidation of the unsubstituted β-carbon of the phenylpropionic acid head group was implicated in the high clearance, and thus a series of benzofurans was designed to improve the pharmacokinetic (PK) parameters of this series by providing increased rigidity and increased steric hindrance around the metabolically labile β-carbon. Further optimization resulted in 3, a GPR40 agonist with slightly diminished potency (EC 50 ¼ 14 nM) in vitro, but with greatly improved PK parameters in rats (F ¼ 76%; Cl ¼ 34 mL/h/kg; AUC po ¼ 65 μgÁh/mL).…”