Discovery of the Potent, Selective, Orally Available CXCR7 Antagonist ACT-1004-1239

The chemokine receptor
CXCR7, also known as ACKR3, is a seven-transmembrane
G-protein-coupled receptor (GPCR) involved in various pathologies
such as neurological diseases, autoimmune diseases, and cancers. By
binding and scavenging the chemokines CXCL11 and CXCL12, CXCR7 regulates
their extracellular levels. From an original high-throughput screening
campaign emerged hit 3 among others. The hit-to-lead
optimization led to the discovery of a novel chemotype series exemplified
by the trans racemic compound 11i. This series provided
CXCR7 antagonists that block CXCL11- and CXCL12-induced ß-arrestin
recruitment. Further structural modifications on the trisubstituted
piperidine scaffold of 11i yielded compounds with high
CXCR7 antagonistic activities and balanced ADMET properties. The effort
described herein culminated in the discovery of ACT-1004-1239 (28f). Biological characterization of ACT-1004-1239 demonstrated
that it is a potent, insurmountable antagonist. Oral administration
of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase
of plasma CXCL12 concentration.