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

Abstract

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 (EC = 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.

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%).…”

Exploration of the nitrogen heterocyclic periphery around the core of the advanced FFA1 agonist fasiglifam (TAK‐875)

“…Our efforts toward the development of less lipophilic FFA1 agonists have recently focused on the former approach, that is, varying the polar periphery without changing fasiglifam's basic 3‐(4‐benzyloxy)phenylpropionic acid scaffold. [ 15–17 ] In some cases, however, total elimination of centroids of lipophilicity from the peripheral motifs led to a complete ablation of potency (as was the case with compound 5 ). This loss of affinity to the receptor could be drastically reversed by bringing back lipophilic aromatic (as in compounds 6 ) or even adding polar heteroaromatic groups (as in compound 7 ).…”

“…This restoration of potency was shown to be only partly due to new hydrophobic interactions with L54 2.51 , L135 4.54 , and V81 3.27 of the receptor; more considerable (particularly in the case of 7 ) was the additional π stacking interaction with W131 4.50 (Figure 2). [ 15–17 ]…”

“…Mindful of the importance of counterbalancing the addition of polar heterocyclic motifs with aromatic appendages capable of building a network of hydrophobic (free fatty acid‐like) and π stacking interactions with the protein target, we designed three types of appendages. Capitalizing upon the successful use of piperidine peripheral motifs, [ 15–17 ] we set off to explore piperidine‐fused pyrazole 8 , 2‐pyridone 9 , and 2‐alkoxypyridine 10 , which could be elaborated into potential FFA1 agonists via reductive amination reaction with aldehyde 11 whose synthesis on a multigram scale had been performed earlier (Figure 3). [ 18 ] Herein, we report the results of this investigation.…”