1. Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic
- Author
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Elsa De Lemos, Vanessa Quenehen, Laëtitia Cherel, Nicolas Triballeau, Reginald Brys, Stéphane Beaumont, Florilène Soulas, Murielle Manioc, Thierry Christophe, Emanuelle Wakselman, Ellen van der Aar, Natacha Bienvenu, Christelle L’Ebraly, Luc Nelles, Line Oste, Laurent Saniere, Fatoumata Djata, Stéphanie Lavazais, Philippe Delerive, Stephen Robert Fletcher, Steve De Vos, Mathieu Rafaël Pizzonero, Sabrina Kopiejewski, S. Dupont, Nick Vandeghinste, Jean-Michel Lefrancois, Benedetta Crescenzi, Denis Polancec, Marielle Babel, Pierre Deprez, and Roland Blanque
- Subjects
Azetidine ,Receptors, Cell Surface ,Thiophenes ,Pharmacology ,Rats, Sprague-Dawley ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Free fatty acid receptor 2 ,Animals ,Humans ,Potency ,Structure–activity relationship ,Leukocyte disorder ,Receptor ,ADME ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Antagonist ,Butyrates ,Immune System Diseases ,Biochemistry ,Microsomes, Liver ,Azetidines ,Molecular Medicine ,Leukocyte Disorders - Abstract
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.
- Published
- 2014
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