Editorial [Hot topic: Chemokine Receptors as Targets in Medicinal Chemistry and Drug Discovery (Guest Editors: J. Robert Merritt and Maria Webb)]
Abstract: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.
Document Type: Research Article
Affiliations: Medicinal Chemistry Ligand Pharmaceuticals, Inc. Cranbury, NJ.
Publication date: 2010-09-01