A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection.
BACKGROUND
The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738.


RESULTS
In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.


CONCLUSIONS
SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.
Department of Respiratory and Immunology, Merck Research Laboratories, Kenilworth, NJ 07033, USA. chungherjenh@yahoo.com.
Chung-Her
CH
Jenh
Mary Ann
MA
Cox
Long
L
Cui
Eva-Pia
EP
Reich
Lee
L
Sullivan
Shu-Cheng
SC
Chen
David
D
Kinsley
Shiguang
S
Qian
Seong Heon
SH
Kim
Stuart
S
Rosenblum
Joseph
J
Kozlowski
Jay S
JS
Fine
Paul J
PJ
Zavodny
Daniel
D
Lundell
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D010879:Piperazines; D054367:Receptors, CXCR3; C000608415:SCH 546738; D011718:Pyrazinamide