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

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• 作者：Mathieu Pizzonero ; Sonia Dupont ; Marielle Babel ; St茅phane Beaumont ; Natacha Bienvenu ; Roland Blanqu茅 ; La毛titia Cherel ; Thierry Christophe ; Benedetta Crescenzi ; Elsa De Lemos ; Philippe Delerive ; Pierre Deprez ; Steve De Vos ; Fatoumata Djata ; Stephen Fletcher ; Sabrina Kopiejewski ; Christelle L鈥橢braly ; Jean-Michel Lefran莽ois ; St茅phanie Lavazais ; Murielle Manioc ; Luc Nelles ; Line Oste ; Denis Polancec ; Vanessa Qu茅n茅hen ; Floril猫ne Soulas ; Nicolas Triballeau ; Ellen M. van der Aar ; Nick Vandeghinste ; Emanuelle Wakselman ; Reginald Brys ; Laurent Saniere
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：10044-10057
• 全文大小：531K
• ISSN：1520-4804

文摘

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.