1391075-81-2

Upstream product

• 1131-09-5 benzo[b]thiophene-3-acetic acid 
• 1391077-73-8 2-methylazetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester 
• 1391077-71-6 1-benzyl-2-methylazetidine-2-carboxylic acid ethyl ester 
• 1391077-69-2 2-[benzyl-(2-chloroethyl)amino]propionic acid ethyl ester 
• 1391075-78-7 4-[[1-(2-benzo[b]thiophen-3-yl-acetyl)-2-methyl-azetidine-2-carbonyl]-(4-trifluoromethylbenzyl)-amino]-butyric acid ethyl ester 
• 1391078-59-3 C₁₇H₁₉NO₃S 
• 1391078-83-3 1-(2-benzo[b]thiophen-3-yl-acetyl)-2-methyl-azetidine-2-carboxylic acid 

Relevant academic research and scientific papers

Development and Characterization of a Fluorescent Tracer for the Free Fatty Acid Receptor 2 (FFA2/GPR43)

The free fatty acid receptor 2 (FFA2/GPR43) is considered a potential target for treatment of metabolic and inflammatory diseases. Here we describe the development of the first fluorescent tracer for FFA2 intended as a tool for assessment of thermodynamic and kinetic binding parameters of unlabeled ligands. Starting with a known azetidine FFA2 antagonist, we used a carboxylic acid moiety known not to be critical for receptor interaction as attachment point for a nitrobenzoxadiazole (NBD) fluorophore. This led to the development of 4 (TUG-1609), a fluorescent tracer for FFA2 with favorable spectroscopic properties and high affinity, as determined by bioluminescence resonance energy transfer (BRET)-based saturation and kinetic binding experiments, as well as a high specific to nonspecific BRET binding signal. A BRET-based competition binding assay with 4 was also established and used to determine binding constants and kinetics of unlabeled ligands.

Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: From hit to clinic

FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.

AZETIDINE DERIVATIVES USEFUL FOR THE TREATMENT OF METABOLIC AND INFLAMMATORY DISEASES

Compounds are disclosed that have a formula represented by the following: These compounds may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example inflammatory conditions, infectious diseases, autoimmune diseases, diseases involving impairment of immune cell functions, cardiometabolic diseases, and/or proliferative diseases.