Imidazo-pyrazine derivatives as potent CXCR3 antagonists.

A general way of improving the potency of CXCR3 antagonists with fused hetero-bicyclic cores was identified. Optimization efforts led to the discovery of a series of imidazo-pyrazine derivatives with improved pharmacokinetic properties in addition to increased potency. The efficacy of the lead compound 21 is evaluated in a mouse lung inflammation model.

[1]  James G Krueger,et al.  Potential Role of the Chemokine Receptors CXCR3, CCR4, and the Integrin αEβ7 in the Pathogenesis of Psoriasis Vulgaris , 2001, Laboratory Investigation.

[2]  M. Baggiolini,et al.  Short Communication Increased Expression of IP-10, IL-8, MCP-1, and MCP-3 in Ulcerative Colitis , 1999 .

[3]  R. Stoffel,et al.  Discovery of small molecule benzimidazole antagonists of the chemokine receptor CXCR3. , 2008, Bioorganic & medicinal chemistry letters.

[4]  B. Lemon,et al.  Optimization of the heterocyclic core of the quinazolinone-derived CXCR3 antagonists. , 2008, Bioorganic & medicinal chemistry letters.

[5]  A. Gottlieb,et al.  Psoriasis as a model for T-cell-mediated disease: immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti-CD11a antibody. , 2002, Archives of dermatology.

[6]  Mieke Buntinx,et al.  Synthesis and structure-activity relationship of benzetimide derivatives as human CXCR3 antagonists. , 2008, Bioorganic & medicinal chemistry letters.

[7]  R. Homer,et al.  Regulation of pulmonary fibrosis by chemokine receptor CXCR3. , 2004, The Journal of clinical investigation.

[8]  Helen L Birch,et al.  Development of CXCR3 antagonists. Part 4: discovery of 2-amino-(4-tropinyl)quinolines. , 2008, Bioorganic & medicinal chemistry letters.

[9]  Jakob S. Jensen,et al.  Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. , 1999, The Journal of clinical investigation.

[10]  A. Gottlieb,et al.  Detection of a gamma interferon-induced protein IP-10 in psoriatic plaques , 1988, The Journal of experimental medicine.

[11]  D. Patel,et al.  CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. , 2001, Clinical immunology.

[12]  D. Mahad,et al.  Longitudinal study of chemokine receptor expression on peripheral lymphocytes in multiple sclerosis: CXCR3 upregulation is associated with relapse , 2003, Multiple sclerosis.

[13]  P. Romagnani,et al.  CXCR3-binding chemokines: novel multifunctional therapeutic targets. , 2005, Current drug targets. Immune, endocrine and metabolic disorders.

[14]  Michael G. Johnson,et al.  Antagonists of CXCR3: a review of current progress , 2007 .

[15]  W. Hancock,et al.  Chemokines and their receptors as markers of allograft rejection and targets for immunosuppression. , 2003, Current opinion in immunology.

[16]  Helen L Birch,et al.  Development of CXCR3 antagonists. Part 3: Tropenyl and homotropenyl-piperidine urea derivatives. , 2008, Bioorganic & medicinal chemistry letters.

[17]  F. Rea,et al.  Cxcr3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection. , 2001, The American journal of pathology.

[18]  J. M. Yoffey,et al.  THE LYMPHATIC PATHWAY FROM THE NOSE AND PHARYNX , 1938, The Journal of experimental medicine.

[19]  M. Baggiolini.  Chemokines and leukocyte traffic , 1998, Nature.

[20]  Todd L Graybill,et al.  Camphor sulfonamide derivatives as novel, potent and selective CXCR3 antagonists. , 2009, Bioorganic & medicinal chemistry letters.

[21]  B. Lemon,et al.  Design and optimization of imidazole derivatives as potent CXCR3 antagonists. , 2008, Bioorganic & medicinal chemistry letters.

[22]  G. McMahon,et al.  Expression of the Chemokine Receptor CXCR3 and Its Ligand IP-10 During Human Cardiac Allograft Rejection , 2001 .

[23]  C. Alpers,et al.  Expression of chemokines and chemokine receptors during human renal transplant rejection. , 2001, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[24]  D. Mahad,et al.  Expression of chemokines in the CSF and correlation with clinical disease activity in patients with multiple sclerosis , 2002, Journal of neurology, neurosurgery, and psychiatry.

[25]  R. Stoffel,et al.  Lead identification of 2-iminobenzimidazole antagonists of the chemokine receptor CXCR3. , 2008, Bioorganic & medicinal chemistry letters.

[26]  W. Hancock,et al.  Requirement of the Chemokine Receptor CXCR3 for Acute Allograft Rejection , 2000, The Journal of experimental medicine.

[27]  Feng Xu,et al.  Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3. , 2007, Bioorganic & medicinal chemistry letters.

[28]  R. Ravid,et al.  Multiple sclerosis: a study of CXCL10 and CXCR3 co-localization in the inflamed central nervous system , 2002, Journal of Neuroimmunology.