The chemokine receptors, CCR(5) and CXCR(4), are the primary co-receptors responsible for mediating HIV-1 cell entry. Small molecules that antagonize these receptors utilize a fundamentally different approach for controlling viral replication than most other classes of antiretroviral agents in that they act on host cell factors rather than viral enzymes. Although CCR(5) modulators that demonstrate efficacy in the clinic against HIV have now become available, CXCR(4) antagonist development is at present at a more nascent stage. Due to the ability of HIV to switch between CCR(5) and CXCR(4) entry co-receptors, the development of a CXCR(4) antagonist is probably critical to prolonging the effectiveness of HIV therapies in patients. In addition, CXCR(4) antagonists represent a novel class of drugs that could be used for the treatment of diseases other than HIV/AIDS.
An overview of the most pertinent chemical classes that modulate the CXCR(4) receptor, in addition to discussions of lead compound development.
The review primarily covers patents and patent application publications filed in the past 8 years. However, earlier patents are included to provide a historical context.
The early bicyclam class proved untenable for HIV treatment due to cardiotoxicity and lack of desirable pharmacokinetic properties. Second generation bicyclam mimics have the benefit of oral bioavailability but have, as yet, not proven successful in the clinic. The peptidomimetic analogues discussed capitalize on known receptor binding site interactions, which could lead to the development of potent and orally available CXCR(4) antagonists.
"CXCR4 is characterized by a strong negatively charged extracellular surface, therefore most of the CXCR4 binding agents are highly basic and positively charged. A detailed overview of the available CXCR4 binding agents and CXCR4-based imaging agents can be found elsewhere in the literature (Mosley et al., 2009; Woodard and Nimmagadda, 2011). The majority of the CXCR4 targeted imaging agents to date have originated from the polyphemusin-based peptides and cyclam-based low molecular weight agents. "
[Show abstract][Hide abstract] ABSTRACT: Chemokine/chemokine receptor interactions play diverse roles in cell migration and homeostasis. Emerging evidence suggests that cancer cells co-opt chemokine networks for survival, proliferation, immune evasion, and metastasis. Most of the chemokine receptors are reported to be involved in tumor progression. Given their extensive implication in cancer progression, several chemokine receptor/ligand axes are considered as potential therapeutic targets. This review provides a survey of chemokine receptor expression in cancer and evaluates the potential of chemokine receptor imaging as a tool for molecular characterization of cancer.
Frontiers in Oncology 05/2012; 2:46. DOI:10.3389/fonc.2012.00046
"The CXCR4 entry inhibitors can be divided into three main groups: small antagonist molecules [Mosley et al., 2009], large and small peptide antagonists [Tamamura et al., 2001, 2005; Cluzeau et al., 2007], and chemokine-based agents [Shaheen and Collman, 2004; Kazmierski et al., 2005]. Among the small molecule antagonists, there are at least ten families, consisting of tetrahydroquinolinamine derivatives (with two main categories: the benzimidazoles and imidazopyrimidines ) [Bridger et al., 2002a,b,c, 2003, 2004], phenanthroline derivatives [Catalano et al., 2010; Jenkinson et al., 2010], KRH derivatives [Ichiyama et al., 2003; Murakami et al., 2004; Yamazaki et al., 2003, 2004], macrocycles [Bridger et al., 1999, 2010], AMD bicyclam derivatives [Bridger et al., 1999; De Clercq, 2000; Esté et al., 1999; Egberink et al., 1999; Hatse et al., 2005; Princen et al., 2004], dipicolil amine zinc(II) complexes [Tamamura et al., 2006], peptidomimetic compounds consisting of a common peptidic backbone with various alkyl nitrogenated branches [Kureha, 2004], isothiourea derivatives [Novartis, 2007], pyrimidine derivatives [Ono Pharmaceutical Co, 2007; Taigen, 2006], and amine-based derivatives, either noncyclam amines, such us ethanediamine polyamine compounds [Taigen, 2004; Moyle et al., 2007] and diamine compounds [Teixidó et al., 2006; Pettersson et al., 2008], or monocyclam amines [Pettersson et al., 2010; Rosenkilde et al., 2007]. "
[Show abstract][Hide abstract] ABSTRACT: The lead optimization of a series of N-substituted benzimidazole CXCR4 antagonists is described. Side chain modifications and stereochemical optimization led to substantial improvements in potency and protein shift to afford compounds with low nanomolar anti-HIV activity.
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