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

Abstract

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 containing 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 (EC 50 = 55 nM) was achieved.Four lead compounds (EC 50 range 55 -410 nM) 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.

Sulfonimidamides and Imidosulfuric Diamides: Compounds from an Underexplored Part of Biologically Relevant Chemical Space

“…Infrared spectra were recorded with a Bruker Vertex 70 spectrometer equipped with attenuated total reflection (ATR) accessory. Log D , solubility, and hepatic microsomal stability were measured according to the protocols described previously CCDC…”

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

“…In addition, agonist 82 displayed a good PK profile (CL = 0.27 mL/min/kg, t 1/2, iv = 7.77 hr, AUC po = 82 μg·hr/mL, F = 45%) in rats . The researchers of Saint Petersburg State University prepared a novel series of spirocyclic periphery analogs based on the Prins cyclization . Structures 83 (hEC 50 = 55 nM) and 84 (hEC 50 = 410 nM) exemplify such building blocks.…”

“…172 The researchers of Saint Petersburg State University prepared a novel series of spirocyclic periphery analogs based on the Prins cyclization. 173,174 Structures 83 (hEC 50 = 55 nM) and 84 (hEC 50 = 410 nM) exemplify such building blocks. However, mouse liver microsome instability (83, t 1/2 = 8.5 min; 84, t 1/2 = 23.4 min) of this series was noted, resulting in a bad PK profile for 84 (F = 10.3%).…”

“…However, mouse liver microsome instability (83, t 1/2 = 8.5 min; 84, t 1/2 = 23.4 min) of this series was noted, resulting in a bad PK profile for 84 (F = 10.3%). 173…”

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

“…Spirocyclic moieties in general are considered privileged structures for GPCR ligand design due to their pronounced three-dimensional character, better complementarity to the protein target of interest and lower off-target effects [16]. This prompted us to develop a series of spirocyclic compounds which delivered lead structure 6 [17]. It has a potency of 55 nM which is in sharp contrast with inactive compound 7 where the 1-oxa-9-azaspiro [5.5]undecane periphery is unsubstituted.…”