Current Topics in Medicinal Chemistry - Volume 10, Issue 13, 2010

A book called, “What We Believe but Cannot Prove” by John Brockman compiled articles, like each issue of Current Topics in Medicinal Chemistry (CTMC), by scientists who are recognized as experts in their respective fields. Unlike CTMC, each was a statement of beliefs that the scientist held about 'the edge' of their science. In this editorial we'd like to apply this concept to the field of chemokines. We believe, but cannot prove, that a small molecule chemokine receptor inhibitor will someday become a marketed drug. But that's not hard to believe since Maraviroc is already a marketed drug that targets CCR5. By our way of thinking though, Maraviroc, a valuable addition to the HIV arsenal, interferes with CCR5 to prevent viral binding but is not an inhibitor of CCR5 mediated chemotaxis. So let us more precisely state the belief. We believe, but cannot prove, that a small molecule chemokine receptor inhibitor that interferes with chemotaxis (cell-trafficking) will someday become a marketed drug. This is an important distinction because such a chemokine receptor antagonist could achieve focused suppression of immunity by blocking the trafficking and activation of specific white blood cells. When many of us first began working on chemokine receptor antagonists in the late 1980's and early 1990's, we certainly thought that this would have already been achieved. At that point, there were many players already entering the field and by the millennium many compounds had entered clinical testing- clearly a step toward the ultimate success of a drug. As is all too often the case, demonstration of human efficacy has been the stumbling block in furthering that successful progression. What is the explanation for insufficient efficacy that plagues chemokine antagonists? There are perhaps as many possible explanations as there are receptors. Evolution has crafted chemokine receptors such that there is great variability both between species and within species. The variability plays out not only in receptor homology or lack thereof, but also in coverage and function, such that a receptor like CCR1, strongly associated with monocyte chemotaxis in human, is more involved with neutrophil chemotaxis in rodent. Thus animal models can be even more misleading than usual, and are often precluded except for general toxicity. Evolution has also built in great redundancy — a good thing when you need to fight off infection from the latest invader, not so good if you are building a molecule to selectively target a specific receptor and suppress inflammation. Thus with receptors like CXCR2 and CXCR1 both activated by some of the same chemokines and both involved with neutrophil chemotaxis and activation, a dual antagonist, or at least, a selective antagonist with very high and sustained levels of occupancy may be required. A 3rd reason is the feedback loops with which biology endowed us. Specifically, effective blockade of one receptor, may increase the chemokine concentration and therefore signaling across receptors. Nevertheless, there are a number of chemokine receptor antagonists still in the clinic. The hypothesis has not been fully tested and the verdict is not in. In this issue, we will attempt to review the current status of the field with an eye toward chemokine receptor antagonists that are still in development and also new research opportunities. We begin with Jinqi Liu's overview of small molecule antagonists for various CCRs primarily focused on anti-inflammatory indications. Continuing with the CCR theme, the next three manuscripts take an in depth look at CCRs 1, 2 and 5. Ron Gladue discusses various CCR1 antagonists that have moved on to late stage development and clinical trials, including Pfizer's early compound, CP-481715. Mary Struthers and Alexander Pasternak from Merck have provided an extensive review of CCR2 antagonists and what has been learned from clinical failures. Remy Lemoine and Jutta Wanner from Roche have covered the full history of CCR5 antagonists from marketed anti- HIV therapeutics to current elusive efforts towards treatment of inflammatory disorders. Next we move to CXCR2 with a paper from Michael Dwyer and Purakattle Biju covering recent progress for antagonists including their promising treatment for COPD, Merck's SCH527123. We close with a manuscript from James Pease and Richard Horuk about the potential for, and putative benefits of, dual chemokine receptor antagonists. We express out great thanks to the authors for their contributions and hope you enjoy this issue of Current Topics in Medicinal Chemistry.

CC chemokines and their receptors play a key role in mediating both physiological and pathological processes. Chemokine receptors have been widely recognized as attractive drug targets by the pharmaceutical industry. A number of small molecule chemokine receptor antagonists have been developed for different disease indications, including rheumatoid arthritis (RA). This article describes the pharmacological evidence to support the therapeutic potential of targeting chemokine receptors, and highlights some of the recent progress in the field of developing small molecule antagonists for CC chemokine receptors aiming for RA and other disease applications. Furthermore, with the unsatisfactory clinical success so far, potential solutions leading to better success rates are also discussed.

The identification of chemokines and their receptors as potent mediators of leukocyte infiltration raised interest in the potential role of these proteins on disease pathogenesis. This is exemplified by the chemokine receptor, CCR1, which has been shown to be up-regulated in a number of human diseases, the implications of which have been suggested by animal models where inhibition of CCR1 or its ligands have shown beneficial effects. These data support the possibility that a CCR1 antagonist will provide therapeutic benefit to patients with inflammatory diseases. Over the last several years, several of these antagonists entered clinical trials, including CP-481,715 (Pfizer) and MLN3897 (Millennium) for rheumatoid arthritis, BX471 (Berlex / Scherring AG) for multiple sclerosis, and AZD-4818 (Astra-Zeneca) for COPD. This review will describe the evidence that supported the role of CCR1 in these diseases, the results from clinical trials, and provide perspectives on what has been learned from these trials for potential application / consideration to other studies with chemokine receptor antagonists.

Inhibition of CCR2 has been considered as a target for multiple therapeutic diseases including autoimmune disease, atherosclerosis, pain, and metabolic disease, based in part on the critical role this receptor plays on monocyte migration. Numerous companies have reported programs to identify CCR2 antagonists. Common challenges to the development of CCR2 agents have included poor activity at the rodent receptor and selectivity for both other chemokine receptors and ion channels. This review summarizes the rationale for targeting CCR2 in disease, the recent progress in the identification of potent and select CCR2 antagonists, and the current status of clinical trials for CCR2 agents.

This review will focus on the discovery and clinical development of small molecule antagonists of CCR5 for the treatment of HIV-1/AIDS, as well as for the potential treatment of inflammatory diseases. In particular, we will focus on the specific medicinal chemistry problems that were faced during the discovery of the molecules. We will also describe limited data from clinical development phases focusing on specific issues that arose during the clinical trials. Finally, we will touch on the mechanism of action of CCR5 antagonists.

The CXC chemokine receptor 2 (CXCR2) has attracted a considerable amount of attention as a target for therapeutic intervention due the key role this receptor plays in a number of inflammatory disorders. Over the past decade, several classes of potent, selective CXCR2 receptor antagonists have been developed as potential anti-inflammatory agents. These small-molecule chemokine receptor antagonists have demonstrated the ability to inhibit CXCR2-mediated recruitment of inflammatory cells in vitro as well as shown efficacy in vivo in various animal models of inflammation. In addition, several of the most advanced CXCR2 receptor antagonists have recently demonstrated promising proof-of-activity results in early human clinical trials. This review details the discovery and development of the 3,4-diaminocyclobut-3- ene-1,2-dione-based CXCR2 receptor antagonist class including SCH 527123 which is currently in mid-stage clinical evaluation. The medicinal chemistry efforts leading to the discovery of SCH 527123, the in vitro and in vivo pharmacology for this compound, and an overview of the clinical evaluation of SCH 527123 will also be discussed.

A major function of the chemokine system is to coordinate the recruitment of leukocytes to specific locations within the tissues. The involvement of chemokine receptors in a multitude of inflammatory diseases, coupled with their belonging to the highly “druggable” GPCR superfamily, makes them excellent candidates for the development of novel drugs by the pharmaceutical industry. Despite descriptions in the literature of many specific small molecule chemokine receptor antagonists, none have yet shown efficacy in the clinical inflammatory setting. In this article, we discuss the successes and failures of chemokine receptor antagonists in the clinic and review a subset of molecules that are documented as having activity at two or more chemokine receptors. It may be that a more permissive approach, targeting several chemokine receptors with a single molecule will provide the next generation of anti-inflammatory drugs.