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6.28.8.3.2 Chemokine receptor antagonists

Chemokines belong to a family of chemotactic cytokines that direct the migration of immune cells toward sites of inflammation. They are divided into two major (CXC and CC) and two minor (C and CX3C) groups dependent on the number and spacing of the first two conserved cysteine residues. They mediate their biological effects by binding to cell surface receptors, which belong to the 7TM G protein coupled-receptor superfamily.107 As an additional means for modulating the ingress of activated lymphocytes to the GI tract in patients with inflammation, the development of specific chemokine receptor antagonists has been increasing in pace.

In IBD there is evidence of contribution of multiple chemokine receptors in leukocyte recruitment to the gut. The reported increased recruitment of CCR2 + CD4+ and CCR5 + CD4 + T cells in biopsy samples from IBD patients, for instance, is consistent with the observations of increased mucosal MIP-1a/b, RANTES, and MCP-1 expression.

Furthermore, CCR5 and CCR2 knockout mice are resistant to the effects of DSS-induced colitis. CCR1, CCR2, and CCR5 have overlapping chemokine specificity, coligating and transducing signals alone from MIP-1a/b, RANTES, and MCP-1-4. To a greater or lesser extent all these chemokines have been implicated in the disease state. Remarkably few experimental studies have assessed the contribution of CCR1 directly in the pathophysiology of IBD, yet there is a quite large and diverse array of potent and selective nonpeptide CCR1 antagonists described. The 2-methylpiperazine BX-471 (49) (IC50 = 2nM), the quinoxaline-2-carboxylic acid derivative CP-481715 (50) (Kd = 0.2 nM; IC50 = 74 nM), and a series of pyridylbenzoxepines, typified by 51 (Ki = 2.3 nM) for instance displace MIP-1b, RANTES, and MCP-3 with high-affinity functional potency.109-111 BX-471 has anti-inflammatory activity in experimental models of MS and renal fibrosis. There is reported clinical development of a humanized anti-CCR2 mAb, MLN-1202, for RA and MS: however, apart from several series of cyclopentanes (of which 52 is a typical example; reported IC50<1 mM112'113); the chemical landscape for CCR2 is less well defined. The finding that CCR5 is a major co-receptor for gp120-dependent HIV-1 entry, and that individuals carrying the A32 polymorphism are protected from infection, has resulted in the rapid development of specific CCR5 antagonists.114 UK-427857/Maraviroc (53) is one of the most clinically progressed agents and prevents gp120 binding and viral replication (IC50 = 43 and 0.2 nM, respectively). Several other series of potent antagonists which also block viral replication, typified by 54 (Sch-D) (IC50 = 0.45 nM), 55 (IC50 = 0.3 nM), and 56 (GW-873140) (IC50 = 1 nM), have also been reported. Although CCR5 knockout mice appear to be protected from the effects of DSS-induced colitis, the D32 polymorphism appears equally in the IBD and healthy population,115 suggesting that antagonism of CCR5 may not be sufficient to attenuate the disease process and that further multiple pathways contribute to the clinical condition.

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