Optimization of First-in-Class Dual-Acting FFAR1/FFAR4 Allosteric Modulators with Novel Mode of Action.

ABSTRACT: The free fatty acid receptors FFAR1 and FFAR4 are considered promising therapeutic targets for management of metabolic and inflammatory diseases. However, there is a need for entirely novel chemical scaffolds, since many of the highly similar lipophilic chemotypes in development have been abandoned by the pharmaceutical industry, due to toxic effects on hepatocytes and β-cells. Our group has recently reported the discovery of a 1,3,5-triazine-2-amine-based compound that acts as an allosteric agonist on FFAR1. Here, we present the synthesis and investigation of the structure-activity relationship of an extensive set of analogues of which many display dual-acting agonist properties for both FFAR1 and FFAR4. In several rounds of optimization, we discovered multiple analogues with single-digit

SUBMITTER: Luckmann M 

PROVIDER: S-EPMC9743428 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature