Review
Chemokines, chemokine receptors and small-molecule antagonists: recent developments

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Abstract

The physiological roles of chemokine receptors have expanded beyond host defense and now represent important targets for intervention in several disease indications. Chemokine receptors have joined the ranks of other members of the G-protein-coupled receptor (GPCR) family in therapeutic potential as small-molecule chemokine receptor antagonists move from discovery to the clinic. Chemokine receptors belong to the rhodopsin family of GPCRs and, as such, are expected to be closely related in structure to other Class A members. In this review, we summarize information that is pertinent to chemokine receptors as therapeutic targets, the status of low molecular weight antagonists in clinical development, molecular modeling of receptor–small-molecule interactions, and the challenges that face drug discovery and development programs.

Section snippets

Chemokines and receptors

Initially, in the late 1980s, chemokines and their receptors were described as key players in host defense, based on their potent activity in leukocyte migration and recruitment. Chemokines are classified (CC, CXC, CX3C and XC) based on the number and sequential relationship of the first two of four conserved cysteine residues. Initially, it was envisaged that the CXC chemokine receptors would be important targets for acute inflammation and CC chemokine receptors would be important targets for

Assigning potential targets of disease states

Because of the inherent complexity of the chemokine–chemokine-receptor axis, determined by expression patterns, post-translational modifications and the overlapping ligand–receptor specificities, the primary indication of therapeutic potential for this family comes from examining results from knockout animals in models of human disease states. However, because chemokines and chemokine receptors have roles in hematopoiesis and development, responses in knockout animals might not reflect the

General features of chemokine receptor antagonists

Chemokine receptor antagonists appear to share common features. First, the majority of these molecules contain a basic region, exemplified by the presence of piperidine, piperazine, spiropiperidine, pyrrolidine, guanidine, quaternary nitrogen or bicyclam groups. Second, many of them appear to have a preference for halogen-modified aromatic rings. The molecular basis for potent antagonism of CCR2 by the Roche spiropiperidine-derived compounds appears to involve an ionic interaction of the basic

Challenges facing inhibitor development programs

Because chemokine receptors are closely related to other Class A GPCR members it is not surprising to find examples of small-molecule antagonists that cross-react with other GPCRs. This appears to be particularly true for several chemokine receptor antagonists, which cross-react with biogenic amine receptors. For example, Schering-Plough's piperazine-based CCR5 inhibitors cross-react with muscarinic acetylcholine receptors [42], whereas Roche's CCR2 spiropiperidine inhibitor series cross-reacts

Concluding remarks

In the late 1980s scientists isolated the signaling molecules, termed chemokines, that allowed leukocytes to communicate with one another and seek out and destroy invading pathogens. However, the immune response is a double-edged sword and can, under some circumstances, be activated inappropriately and targeted towards normal, healthy tissue, which leads to autoimmunity and disease. In the space of 6 years, numerous, non-peptide chemokine receptor antagonists have been identified and some have

Acknowledgements

We would like to acknowledge researchers whose work is not specifically referenced owing to space limitations.

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