Chemokines are a family of signaling proteins secreted by cells. Their major role is to act as chemoattractants to guide the migration of immune cells through a mechanism called chemotaxis. Differences in chemokine concentrations in blood and tissues are sensed by cells expressing on their surface the cognate receptor of the chemokine, resulting in directed migration along the chemokine gradient. The CXCR3 receptor, a class A G protein-coupled receptor (GPCR), binds to the three pro-inflammatory chemokines CXCL9, CXCL10 and CXCL11 and is a key component of the adaptive immune response. We and others¹ started programs aiming at the discovery of small molecules to block the CXCR3 axis. Encouraging data recently disclosed with the CXCL10 monoclonal antibody eldelumab² in combination with methotrexate in a phase II trial for rheumatoid arthritis further strengthened our interest in this target. Herein we present the identification and optimization of thiazolo-piperazine analogs as potent CXCR3 antagonists and share in vivo efficacy data in a proof-of-mechanism mouse model of lung inflammation.

[1] Stephen P. Andrews, Rhona J. Cox. Small Molecule CXCR3 Antagonists. J. Med. Chem. 2016, 59, 2894-2917.
[2] Michael Yellin, Igor Paliienko, Andra Balanescu, Semen Ter-Vartanian, Vira Tseluyko, Li-An Xu, Xiaolu Tao, Pina M. Cardarelli, Heidi Leblanc, Geoff Nichol, Codrina Ancuta, Rodica Chirieac, Allison Luo. A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2012, 64, 1730-1739.