Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic.
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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Mathieu
M
Pizzonero
Sonia
S
Dupont
Marielle
M
Babel
Stéphane
S
Beaumont
Natacha
N
Bienvenu
Roland
R
Blanqué
Laëtitia
L
Cherel
Thierry
T
Christophe
Benedetta
B
Crescenzi
Elsa
E
De Lemos
Philippe
P
Delerive
Pierre
P
Deprez
Steve
S
De Vos
Fatoumata
F
Djata
Stephen
S
Fletcher
Sabrina
S
Kopiejewski
Christelle
C
L'Ebraly
Jean-Michel
JM
Lefrançois
Stéphanie
S
Lavazais
Murielle
M
Manioc
Luc
L
Nelles
Line
L
Oste
Denis
D
Polancec
Vanessa
V
Quénéhen
Florilène
F
Soulas
Nicolas
N
Triballeau
Ellen M
EM
van der Aar
Nick
N
Vandeghinste
Emanuelle
E
Wakselman
Reginald
R
Brys
Laurent
L
Saniere
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D001384:Azetidines / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D002087:Butyrates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007154:Immune System Diseases; D020128:Inhibitory Concentration 50; D007960:Leukocyte Disorders; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001384:Azetidines; D002087:Butyrates; D011956:Receptors, Cell Surface; D013876:Thiophenes; C000595478:4-(((R)-1-(benzo(b)thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl)-(3-chloro-benzyl)-amino)-butyric acid; C473103:FFAR2 protein, human; D043562:Receptors, G-Protein-Coupled