Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic

• Published in: Journal of medicinal chemistry Vol. 57; no. 23; pp. 10044 - 10057
• Main Authors: Pizzonero, Mathieu, Dupont, Sonia, Babel, Marielle, Beaumont, Stéphane, Bienvenu, Natacha, Blanqué, Roland, Cherel, Laëtitia, Christophe, Thierry, Crescenzi, Benedetta, De Lemos, Elsa, Delerive, Philippe, Deprez, Pierre, De Vos, Steve, Djata, Fatoumata, Fletcher, Stephen, Kopiejewski, Sabrina, L’Ebraly, Christelle, Lefrançois, Jean-Michel, Lavazais, Stéphanie, Manioc, Murielle, Nelles, Luc, Oste, Line, Polancec, Denis, Quénéhen, Vanessa, Soulas, Florilène, Triballeau, Nicolas, van der Aar, Ellen M, Vandeghinste, Nick, Wakselman, Emanuelle, Brys, Reginald, Saniere, Laurent
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-12-2014
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Azetidines - chemical synthesis; Azetidines - metabolism; Azetidines - pharmacokinetics; Azetidines - pharmacology; Butyrates - chemical synthesis; Butyrates - pharmacokinetics; Butyrates - pharmacology; Humans; Immune System Diseases; Inhibitory Concentration 50; Leukocyte Disorders; Mice; Microsomes, Liver - metabolism; Rats, Sprague-Dawley; Receptors, Cell Surface - antagonists & inhibitors; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - pharmacokinetics; Thiophenes - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5012885

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.