Discovery of Chromane Propionic Acid Analogues as Selective Agonists of GPR120 with in Vivo Activity in Rodents

Abstract

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated in vivo. Results of these efforts suggest that chromane propionic acid 18 is a suitable tool molecule for further animal studies. Compound 18 is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/ knockout GPR120 mouse oGTT studies.

FFA4/GPR120: Pharmacology and Therapeutic Opportunities

“…More recently reported compounds have provided greater levels of selectivity. For example, Adams et al [54] reported a chromane propionic acid-based agonist series where specific members are at least 300-fold more selective for both human and mouse FFA4 compared with FFA1. Similarly, Sparks et al [55] described a phenylpropanoic acid series with an exemplar compound showing between 40- and 130-fold selectivity over FFA1 across human, mouse, and rat orthologues.…”

“…However, not all of the more recently described ligands are suitable for in vivo studies due to poor pharmacokinetic and pharmacodynamic properties [56] . By contrast, although not currently available from commercial suppliers, phenylpropanoic acid ‘compound 29’ [55] , nonacidic sulfonamide ‘compound 34’ [57] , and chromane propionic acid ‘compound 18’ [54] have each been used for rodent in vivo studies to explore glucose handing and aspects of regulation of insulin sensitivity. In each case, these have provided clear support for an important role of FFA4 in the regulation of glucose homeostasis.…”

Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators

“…For several of these variant chemotypes, compounds with favorable pharmacokinetic properties could be developed, enabling in vivo experiments to study their effects as antidiabetic or weight-lowering drugs. These studies are reported in the patent literature or peer-reviewed journals confirming the insulin-sensitizing [ 175 , 177 , 178 ] or weight-reducing [ 175 ] effects of FFAR4 agonists in rodents. In spite of these encouraging data from relevant in vivo models, so far no clinical trials have been reported for FFAR4 agonists; therefore, the development of an FFAR4 agonist suitable for treatment of patients is still awaited.…”

“…The ortho-biphenyl core of TUG-891 was then the starting point for further compound optimization programs yielding more selective and, for in vivo studies, suitable FFAR4 agonists [ 174 , 175 ]. Further, FFAR4 agonists were derived from PPARγ agonists [ 176 ] or discovered in HTS campaigns and subsequently optimized [ 177 , 178 ]. For several of these variant chemotypes, compounds with favorable pharmacokinetic properties could be developed, enabling in vivo experiments to study their effects as antidiabetic or weight-lowering drugs.…”

GPR120/FFAR4 Pharmacology: Focus on Agonists in Type 2 Diabetes Mellitus Drug Discovery

“… 115 Starting from the promising results of compound 23 , 115 the subsequent optimization process consisted of the replacement of the benzofuran moiety with a chromane system, characterizing compounds 24 – 25 ( Figure 6 ). 116 The effect of several modifications on the chromane propanoic acid chain furnished compounds with abolished activity in both hGPR120 IP1 and β-arrestin assays (CHO-K1). Chromane enantiomers R and S were well tolerated and so was the switch to a cyclopropanoic acid (EC 50 = 69–160 nM in the IP1 assay), although bioisosteres such as tetrazole reached worse potency.…”