Structural basis for the agonist action at free fatty acid receptor 1 (FFA1R or GPR40)

Abstract

G-protein-coupled receptor 40 (GPR40) was recently identified as an interesting target for treatment of type 2 diabetes. The high level of expression in pancreatic beta cells and the dependence of glucose on stimulating the secretion of insulin led to great excitement in this field. The identification of this target was followed by the development of a series of agonists with great potential for the treatment of diabetes. All known agonists have the presence of a pharmacophoric carboxylic acid group in their structure, which makes several polar interactions at the binding site of this receptor. In this report, we provide a review of the structure-activity relationships of GPR40 agonists with a focus on the main strategies of medicinal chemistry used to develop each one of the main structural patterns exploited for this purpose. Additionally, we provide a general model for the design of GPR40 ligands that can help researchers to follow up some strategies and implement them in the development of novel agonists of this receptor.

Discovery of Second Generation RORγ Inhibitors Composed of an Azole Scaffold

“…However, such a tactic may sacrifice metabolic stability of the ligand; therefore pursuing such van der Waals interactions was not a practical option in this case. Alternatively, implementation of a polar functionality outside the binding pocket is a viable strategy, and a number of successful examples have been reported in the literature. , The X-ray cocrystal structure of our first generation inhibitor suggested a substituent at the β-position of the propanoyl moiety would project toward the outside the pocket (Figure ), so we introduced substituents bearing a functional group at the terminus and examined their effects on metabolic stability and other pharmacokinetic parameters.…”

Novel Mechanism of Fatty Acid Sensing in Enteroendocrine Cells: Specific Structures in Oxo‐Fatty Acids Produced by Gut Bacteria Are Responsible for CCK Secretion in STC‐1 Cells via GPR40

“…Except carbon chain length dependency, the structure–activity relationships of fatty acid properties such as degree of unsaturation, position or cis – trans isomerism of double bond(s) have not been established. Although various GPR40 agonists has been developed, none of them possess the structures found in the present study. The present study revealed two distinct structures related to potent activation of GPR40‐mediated CCK secretion in enteroendocrine cells.…”

Patent Highlights April–May 2018

“…Chemically they resemble those from the '575 document closely, with most of the structure -in many cases, including the characteristic terminal carboxycyclopropyl group -preserved. (All known GPR40 agonists contain a pharmacophoric carboxylic acid group in their structure, allowing several polar interactions at the binding site of this receptor [47].) While diabetes clearly is the primary development target for free fatty acid receptor agonists, they might be useful in other therapeutic fields; for antagonists, suppression of inflammatory responses in periodontal diseases could be an example [48].…”