Elsevier

Methods

Volume 29, Issue 4, April 2003, Pages 369-375
Methods

Development and evaluation of pharmacological agents targeting chemokine receptors

https://doi.org/10.1016/S1046-2023(02)00361-4Get rights and content

Abstract

Chemokine receptors belong to one of the most pharmacologically exploited proteins, the G-protein-coupled receptors. Drugs that target these receptors make up greater than 45% of all known marketed medicines. Several excellent reviews published recently have concentrated on the biology, pathophysiology, and molecular mechanisms of action of the chemokines [C. Gerard, B.J. Rollins, Nat. Immunol. 2 (2001) 108; C.R. Mackay, Nat. Immunol. 2 (2001) 95; M. Thelen, Nat. Immunol. 2 (2001) 129] and the reader is directed toward them to gain a thorough understanding of the importance of this growing family of proteins. Although some background will be given here to aid in an understanding of the medical importance of chemokines, this review will focus on the rapid advances that have been made in identifying and characterizing chemokine receptor antagonists, by discussing their efficacy in animal models of disease as well as detailing their progression through human clinical trials. This approach is exemplified by specific reference to CCR1 and CCR5, which are the most advanced chemokine receptor programs.

Section snippets

Chemokines and their receptors

Chemokines belong to a large family of small, chemotactic cytokines characterized by a distinctive pattern of four conserved cysteine residues [2]. 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. Although originally identified on the basis of their ability to regulate the trafficking of immune cells, the biological role of chemokines goes well beyond this simple description of their

Drug development

The development of a drug, from its first identification in a high capacity screen to its approval by the Food and Drug Administration as an authorized therapeutic for use in humans, is a long and arduous process involving numerous stages that include the following steps.

(1) Drug specificity—The drug should have high specificity for the chosen target, i.e., the drug is tested in multiple screens against a variety of related and unrelated enzymes, receptors, etc., to ensure that it is highly

CCR1 antagonists

Insight into the physiological and pathophysiological roles of CCR1 have been provided by studies with potent CCR1 antagonists (Fig. 1, compound 1) [18], [20], [21], [22] and confirmed by targeted gene-disruption studies [23], [24], [25].

Three separate studies with potent CCR1 receptor antagonists have illuminated the role of CCR1 in the pathophysiology of multiple sclerosis and organ transplant rejection [18], [21], [22]. Several potent nonpeptide CCR1 antagonists have been reported (Fig. 1)

CCR5 antagonists

The unmasking, several years ago, of the chemokine receptors CCR5 and CXCR4 as major coreceptors, along with CD4, for HIV-1 invasion provided a strong impetus for the rapid development of chemokine receptor antagonists by the pharmaceutical industry. The early stages of HIV-1 infection appear to involve macrophage-tropic strains of HIV-1, known as R5, which use mainly CCR5 as coreceptors [28].

HIV-1 resistance exhibited by some exposed but uninfected individuals [29] is due, in part, to a 32-bp

Conclusion

The immune system is the first line of defense in infection and disease; however, when this process breaks down defenders become attackers and immune cells can target and destroy normal healthy host cells, resulting in inflammation and leading to autoimmune diseases like multiple sclerosis and diabetes. With the discovery of chemokines and the central role they play in leukocyte recruitment came the realization that small-molecule inhibitors that blocked these effects could be very useful

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