Awm

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Several classes of dual-specificity antagonists have also been described. For instance, TAK-779 (57) is an inhibitor of mouse CXCR3 and CCR5 (IC50 = 3 69 and 236 nM, respectively; the human CCR5 IC50 = 1.4 nM) and displays significant inhibition at the human and mouse CCR2 receptor as well (IC50 = 27 and 24 nM, respectively).11 'n When dosed to DSS-treated mice, TAK-779 (50mgkg_ 1, intradermal) inhibited the recruitment of CD11b + leukocytes to the colon and delayed as well as suppressed the extent on the colonic injury.118

IFN-g-inducible protein-10 (IP-10) and CXCR3 are highly expressed at sites of colitis. CXCR3 is expressed on a fraction of circulating blood T cells, B cells, and NK cells. T cells positive for CXCR3 are mostly CD45RO + memory cells, which express high levels of b1 integrins, and the CXCR3 + /CD4 + Tcell subset is enriched for Th1 cells. As with other chemokine receptors, Tcell activation enhances CXCR3 expression and chemotactic responsiveness. Blockade of IP-10 with an antibody reduces inflammation in IL10 _/_ mice119; a fully human anti-IP10 antibody (MDX-1100) is currently undergoing early clinical evaluation in patients with CD.

One class of quinolines, typified by NBI-74330 (58), blocks the binding of IP-10 and interferon-inducible Tcell alpha chemoattractant (ITAC) (Ki = 1.5 and 3.2 nM, respectively) and CXCR3-dependent Ca2 + mobilization (IC50 = 7-18 nM).120 NBI-74330 was taken from a series of recent disclosures, , in which a lead clinical agent T-487 is putatively exemplified, but whose structure is not yet reported. Despite the encouraging developments in identification of CCR2, CCR5, and CXCR3 antagonists, none so far has been rigorously assessed in experimental models of colitis or clinically in the IBD population. CCR9 antagonists, however, are being progressed clinically for the condition.

The chemokine receptor CCR9 is coexpressed on gut-homing a4b7 lymphocytes and additionally appears to contribute to both T cell activation and the production of pro-inflammatory cytokines, such as IFN-g.123-125 Either depletion of CCR9 or its ligand, CCL25/TECK, impairs the ability of these cells to home properly and attenuates the ileitis observed in the SAMP/Yit mouse model. CCX282/Traficet is currently being evaluated in phase II clinical trials in CD. The structure of the CCX282 is undisclosed, but a series of arylsulphonamides have been reported,128,129 of which 59 is also reported to reduce the onset of disease symptoms in the Mdr1a_ / _ mouse model of colitis (50mgkg_ 1, twice daily subcutaneously).129 The CCR9/TECK interaction appears to confer some regional specialization to the recruitment and regulation of activation of gut-homing lymphocytes. Firstly, TECK expression appears to be restricted to small intestinal epithelial cells specifically, large bowel epithelium appears to be devoid of TECK expression, even at sites of inflammation.125 A far lower proportion of colonic T cells are CCR9 + (20%) than those in the small bowel, a pattern of restriction which suggests that CCR9 antagonists may be an effective modality in the treatment of small bowel inflammatory CD and celiac disease.

Although CD45Rbhi cells from CCR9 "/" mice fail to induce colitis when adoptively transferred into SCID mice, and CCR9 antagonists appear to be effective in treating the colitic phenotype in the Mdrla _ / _ model, clinical studies aimed at investigating CCR9 antagonists in patients with UC are eagerly awaited to determine whether this approach has wider utility in the treatment of IBD and its extraintestinal manifestations.

Finally, gut tropism of a4b7/CCR9+ lymphocytes is imprinted during maturation and activation in secondary lymphoid tissue.127 Their expression can be induced directly by GALT-derived dendritic cells following antigen stimulation, an effect which is suppressed by the retinoic acid receptor-b (RARb) antagonist LE135 (60).130 Furthermore, as populations of splenic and Peyer's patch a4b7+ CD4+ T cells are dramatically reduced in retinoic acid-deficient mice, these findings further point to a possible involvement in the RAR/RXR pathway in imprinting gut-homing specificity.

6.28.8.3.3 Sphingosine 1-phosphate receptor modulators

In contrast to approaches that suppress lymphocyte recruitment to the intestinal lamina propria, an alternative strategy has emerged from studies of the novel immunosuppressant FTY720 (61).131 Currently in phase III clinical studies for transplant rejection, FTY720 is a founding member of the class of sphingosine 1-phosphate (S1P) receptor agonists. Chronic agonism at S1P receptors expressed on thymocytes and lymphocytes causes desensitization and receptor internalization. As circulating S1P is an obligatory egress signal for lymphocytes leaving lymphoid organs, in the absence of S1P1/Edg1 receptor the cells are retained, inducing a peripheral lymphopenia. As such FTY720, and others of its class, do not appear to act as classical immunosuppressants, as B and Tcell function per se is unaffected. In the IL10_7_ models of spontaneous colitis, FTY720 (orally for 4 weeks) reduced the severity of inflammation.132 FTY720, however, is a nonselective S1P receptor agonist and also activates the inward rectifying K+ channel and this may, in part, contribute to the negative chronotropic effects FTY720 has on isolated perfused guinea pig heart and the bradycardia reported clinically. In preclinical models, KRP-203 (62) has shown a reduced tendency to induce bradycardia, while inducing lymphopenia and maintaining efficacy on acute organ rejection.133 As a divergence from these amino-propanolol derivatives, Merck has reported on a series of oxadiazoles, typified by 63, which possess > 100-fold selectivity for S1P1/ Edg1 over the cardiac S1P3/Edg3 receptor.134

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