Guillaume Dutheuil

N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model

Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp3) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (ΔLLE = 0.3, ΔFsp3 = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.

CCDC 872138: Experimental Crystal Structure Determination

Related Article: Guillaume Dutheuil, Camille Pierry, Emilie Villiers, Samuel Couve-Bonnaire and Xavier Pannecoucke|2013|New J.Chem.|37|1320|doi:10.1039/C2NJ40891K