Current Topics in Medicinal Chemistry - Volume 14, Issue 13, 2014

The human immunodeficiency virus (HIV) causes acquired immumodeficiency syndrome (AIDS), one of the worst global pandemic. The virus infects human CD4 T cells and macrophages, and causes CD4 depletion. HIV enters target cells through the binding of the viral envelope glycoprotein to CD4 and the chemokine coreceptor, CXCR4 or CCR5. In particular, the CCR5-utilizing viruses predominate in the blood during the disease course. CCR5 is expressed on the surface of various immune cells including macrophages, monocytes, microglia, dendric cells, and active memory CD4 T cells. In the human population, the CCR5 genomic mutation, CCR5Δ32, is associated with relative resistance to HIV. These findings paved the way for the discovery and development of CCR5 inhibitors to block HIV transmission and replication. Maraviroc, discovered as a CCR5 antagonist, is the only CCR5 inhibitor that has been approved by both US FDA and the European Medicines Agency (EMA) for treating HIV/AIDS patients. In this review, we summarize the medicinal chemistry and clinical studies of Maraviroc.

CCR5, a member of G protein-coupled receptors superfamily, plays an important role in the HIV-1 entry process. Antagonism of this receptor finally leads to the inhibition of R5 strains of HIV entry into the human cells. The identification of CCR5 antagonists as antiviral agents will provide more option for HAART. Now, more than a decade after the first small molecule CCR5 inhibitor was discovered, great achievements have been made. In this article, we will give a brief introduction of several series of small molecule CCR5 antagonists, focused on their appealing structure evolution, essential SAR information and thereof the enlightenment of strategies on CCR5 inhibitors design.

Chemokines constitute a family of small heparin-binding proteins which orchestrate the infiltration of leukocytes during inflammation, but also directly influence other physiological and pathophysiological processes. In humans, more than 40 chemokines are known binding to around 18 G-protein-coupled receptors. A non-redundant role of certain chemokines and their receptors has been identified within the last years in inflammation and host defense. Among chemokine receptors, the CC chemokine receptors CCR1 and CCR2 have been shown to play a crucial role in these processes. Importantly, these receptors have already been targeted by specific antagonists in early human trials for autoimmune and infectious diseases. Although most of these antagonists failed to show any significant efficacy in the clinic, the knowledge of their biological effects could henceforth offer new avenues with optimal strategies for producing successful therapeutics.

While a number of agents directed at chemokine receptors have entered clinic trials, the vast majority of these have failed, and the enthusiasm for this class of drugs has been attenuated. To date, there are two drugs that inhibit chemokine receptors approved by the FDA. The first to be approved in 2007 was maraviroc (brand name Selzentry, or Celsentri outside the US) which targets CCR5 and is used for the treatment of HIV infection. The second is plerixafor (Mozobil) which was approved in 2008, targets CXCR4, and is used for the mobilization of hematopoietic stem cells. This review will focus on the CC chemokine receptors CCR1 and CCR5. These G protein coupled receptors are both activated by a relatively large number of chemokines, most of which overlap. While most of the drugs for CCR1 have been assessed in the context of autoimmune diseases like multiple sclerosis and rheumatoid arthritis, and those for CCR5 were examined for HIV-infection, we review the role of these receptors in relation to cancer. Recently introduced pharmacophores that serve as agonists or antagonists for the receptors are presented. Efforts to exploit polypharmacology approaches using promiscuous compounds that target more than one receptor are also considered.

The chemokine receptor CXCR4 is required for the entry of human immunodeficiency virus type 1 (HIV-1) into target cells and for the development and dissemination of various types of cancers, including gastrointestinal, cutaneous, head and neck, pulmonary, gynecological, genitourinary, neurological, and hematological malignancies. The T-cell (T)-tropic HIV-1 strains use CXCR4 as the entry coreceptor; consequently, multiple CXCR4 antagonistic inhibitors have been developed for the treatment of acquired immune deficiency syndrome (AIDS). However, other potential applications of CXCR4 antagonists have become apparent since its discovery in 1996. In fact, increasing evidence demonstrates that epithelial and hematopoietic tumor cells exploit the interaction between CXCR4 and its natural ligand, stromal cellderived factor (SDF)-1α, which normally regulates leukocyte migration. The CXCR4 and/or SDF-1α expression patterns in tumor cells also determine the sites of metastatic spread. In addition, the activation of CXCR4 by SDF-1α promotes invasion and proliferation of tumor cells, enhances tumor-associated neoangiogenesis, and assists in the degradation of the extracellular matrix and basement membrane. As such, the evaluation of CXCR4 and/or SDF-1α expression levels has a significant prognostic value in various types of malignancies. Several therapeutic challenges remain to be overcome before the use of CXCR4 inhibitors can be translated into clinical practice, but promising preclinical data demonstrate that CXCR4 antagonists can mobilize tumor cells from their protective microenvironments, interfere with their metastatic and tumorigenic potentials, and/or make tumor cells more susceptible to chemotherapy.

Dysregulated leukocyte recruitment is believed to be a key contributor to various acute and chronic inflammatory disorders which can lead to serious pathological consequences. Chemokines are small molecular weight proteins that have been shown to be imperative in the direction of leukocytes to the sites of inflammation. In humans, several of these chemokines (CXCL8 and CXCL1) are elevated in inflammatory disorders such as asthma, arthritis, and chronic obstructive pulmonary disease (COPD). These chemokines modulate their downstream effects thru G-protein coupled receptors, such as CXCR2, making the identification of small-molecule antagonists of this receptor attractive towards developing novel therapies to treat inflammatory conditions. Since the first report of a CXCR2 receptor antagonist in 1998, there has been a considerable effort conducted mainly in the pharmaceutical industry to identify novel classes of CXCR2 receptor antagonists. Over a dozen distinct classes of CXCR2 receptor antagonists have been reported in the literature to date with a number of these compounds having reached mid-stage clinical trials. This review will provide a broad overview the medicinal chemistry efforts over the past 15 years towards the identification of CXCR2 receptor antagonists. The discussion will focus upon the early preclinical space covering the structure activity relationships (SAR), pharmacology, as well in preclinical in vivo evaluation for the different series of CXCR2 receptor antagonists. In addition, the available clinical data for the most advanced compounds in the clinic will be discussed and along with a perspective of the area moving forward.

Increasing evidence has shown that chemokine receptors may form functional dimers with unique pharmacological profiles. A common practice to characterize such G protein-coupled receptor dimerization processes is to apply bivalent ligands as chemical probes which can interact with both receptors simultaneously. Currently, two chemokine receptor dimers have been studied by applying bivalent compounds: the CXCR4-CXCR4 homodimer and the CCR5-MOR heterodimer. These bivalent compounds have revealed how dimerization influences receptor function and may lead to novel therapeutics. Future design of bivalent ligands for chemokine receptor dimers may be aided with the recently available CXCR4 homodimer, and CCR5 monomer crystal structures by more accurately simulating chemokine receptors and their dimers.

Natural products are rich sources of structure-diversified, selective, and potent molecules with a variety of biological activities. Among them, nearly forty compounds have been reported to antagonize binding of chemokines to chemokine receptors, or inhibit functions of chemokines on their receptors. This review covers the chemical structures, biological activities, and structure-activity relationships of these natural products as chemokine receptor antagonists. Three compounds which interact with chemokines, or mediate gene expressions/functions of chemokines are also presented. Due to the complexity of the chemokine receptor/chemokine system in regulating various biological processes, development of therapeutic agents targeting this system remains quite challenging. Nevertheless, some of these natural products can serve as valuable tools or leads to further advance the knowledge and research in this area.