Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency.

A series of nine compounds based on 3-[4-(benzyloxy)phenyl]propanoic acid core containing a 1-oxa-9-azaspiro[5.5]undecane periphery was designed, synthesized and evaluated as free fatty acid 1 (FFA1 or GPR40) agonists. The spirocyclic appendages included in these compounds were inspired by LY2881835, Eli Lilly's advanced drug candidate for type II diabetes mellitus that was in phase I clinical trials. These polar spirocyclic, fully saturated appendages (that are themselves uncharacteristic of the known FFA1 ligand space) were further decorated with diverse polar groups (such as basic heterocycles or secondary amides). To our surprise, while seven of nine compounds were found to be inactive (likely due to the decrease in lipophilicity, which is known to be detrimental to FFA1 ligand affinity), two compounds containing 2-pyridyloxy and 2-pyrimidinyloxy groups were found to have EC50 of 1.621 and 0.904 µM, respectively. This result is significant in the context of the worldwide quest for more polar FFA1 agonists, which would be devoid of liver toxicity effects earlier observed for a FFA1 agonist fasiglifam (TAk-875) in clinical studies.

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835.

The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long-chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC50=55nM) was reached. Four lead compounds (EC50 range 55-410nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F=10.3%) and plasma levels achieved on oral administration.

Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835.

A series of spirocyclic compounds inspired by Eli Lilly's phase 1 antidiabetic FFA1 receptor agonist LY2881835 was designed to include polar aromatic periphery groups and explore a possibility of building additional contacts with the target near the agonist binding site. The frontrunner compound in the series (9i) was shown to be a potent (EC50 = 260 nM) FFA1 agonist with excellent aqueous (PBS) solubility and good Caco-2 permeability. The observed structure-activity relationships were rationalized by a docking study. The new series significantly expands the ligand landscape for the ongoing quest for new potent and more polar FFA1 agonists as fundamentally new class of therapeutic agents against type 2 diabetes mellitus.