Journal of Medicinal Chemistry p. 10044 - 10057 (2014)
Update date:2022-08-03
Topics:
Pizzonero, Mathieu
Dupont, Sonia
Babel, Marielle
Beaumont, Stéphane
Bienvenu, Natacha
Blanqué, Roland
Cherel, La?titia
Christophe, Thierry
Crescenzi, Benedetta
De Lemos, Elsa
Delerive, Philippe
Deprez, Pierre
De Vos, Steve
Djata, Fatoumata
Fletcher, Stephen
Kopiejewski, Sabrina
Lebraly, Christelle
Lefran?ois, 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
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.
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