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

Mathieu Pizzonero; Sonia Dupont; Marielle Babel; Stéphane Beaumont; Natacha Bienvenu; Roland Blanqué; Laëtitia Cherel; Thierry Christophe; Benedetta Crescenzi; Elsa De Lemos; Philippe Delerive; Pierre Deprez; Steve De Vos; Fatoumata Djata; Stephen Fletcher; Sabrina Kopiejewski; Christelle L'Ebraly; Jean-Michel Lefrançois; Stéphanie Lavazais; Murielle Manioc; Luc Nelles; Line Oste; Denis Polancec; Vanessa Quénéhen; Florilène Soulas; Nicolas Triballeau; Ellen M van der Aar; Nick Vandeghinste; Emanuelle Wakselman; Reginald Brys; Laurent Saniere

doi:10.1021/jm5012885

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

J Med Chem. 2014 Dec 11;57(23):10044-57. doi: 10.1021/jm5012885. Epub 2014 Dec 1.

Affiliation

¹ Galapagos, 102 Avenue Gaston Roussel, 93230 Romainville, France.

PMID: 25380412
DOI: 10.1021/jm5012885

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.

MeSH terms

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

Substances

4-(((R)-1-(benzo(b)thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl)-(3-chloro-benzyl)-amino)-butyric acid
Anti-Inflammatory Agents, Non-Steroidal
Azetidines
Butyrates
FFA2R protein, human
Receptors, Cell Surface
Thiophenes

Supplementary concepts

Neutrophil Chemotactic Response, Abnormal