vicriviroc and aplaviroc

Viral entry is an early stage and specific of the infection in which different viral and cellular targets are accessible to therapeutic treatment. CXCR4 and CCR5 act in this process as coreceptor molecules of HIV for its entry into the host cell. The predominant role played by the CCR5 coreceptor in the transmission and spreading of HIV makes this molecule the target of choice for blocking this mechanism. In the last few years, different specific inhibitors of HIV coreceptors have been generated of which only one, Maraviroc, has been approved for clinical use. The synthetic inhibitors developed act as allosteric antagonists that induce a non-permissive state or configuration of the coreceptor for binding viral envelope-glycoproteins. The CCR5 antagonists act on a wide spectrum of viruses with affinity or tropism for this receptor (virus R5), are absorbed orally and have powerful antiviral activity. However, the optimistic perspective offered by these new molecules has to be moderated due to the possible and expected appearance of viral resistances, on the one hand, and the propagation of viral species with affinity or tropism for the CXCR4 receptor (virus X4). This situation is a reality verified in the first clinical trials with these drugs and they acutely and urgently show the need to have effective and non-toxic CXCR4 inhibitors available to block this alternative viral replication and escape route.

Topics: Adult; Amides; Benzoates; CCR5 Receptor Antagonists; CD4 Antigens; Chemokines, CC; Chemokines, CXC; Clinical Trials as Topic; Cyclohexanes; Diketopiperazines; Drug Design; env Gene Products, Human Immunodeficiency Virus; HIV; HIV Fusion Inhibitors; HIV Infections; Humans; Maraviroc; Membrane Fusion; Models, Molecular; Piperazines; Pyrimidines; Quaternary Ammonium Compounds; Receptors, CCR5; Receptors, CXCR4; Spiro Compounds; Structure-Activity Relationship; Triazoles; Virus Attachment; Virus Internalization

In the context of emerging resistance to antiretroviral agents in HIV medicine, the development of new drugs classes with a novel mechanism of action remains essential. The CCR5 co-receptor antagonists inhibit fusion of HIV with the host cell by blocking the interaction between the gp-120 viral glycoprotein and the CCR5 chemokine receptor. So far, four CCR5 antagonists have entered clinical evaluation, of which three are currently still in different stages of clinical assessment. In this review we compare the clinical efficacy in phase I and II as well as the long-term tolerability, pharmacokinetics and interactions of these new antiretroviral drugs entering HIV practice. Being the first CCR5 antagonist to be investigated in clinical trials, aplaviroc showed initial potent antiviral activity. However, after the occurrence of severe hepatotoxicity in several patients, its development had to be stopped in October 2005. The second CCR5 antagonist, maraviroc, has displayed promising results in phase I, II and III studies, showing a significantly greater decline in HIV RNA and CD4 cell increase compared to placebo, with no clinically relevant differences in safety profile and tolerability. The expanded access program for maraviroc was opened in June 2007 in several European countries. The FDA approved the use of maraviroc for antiretroviral therapy of HIV on the 7th of august, 2007. Finally, the third CCR5 antagonist vicriviroc also showed long-term potent viral activity in phase II studies as long as it was boosted with low-dose ritonavir, with no significant differences in grade 3 and grade 4 adverse effects compared to placebo. The phase II clinical trial amongst ART experienced individuals who received Ritonavir-boosted vicriviroc 10-15 mg qd was unblinded early because of the unexpected occurrence of malignant lymphoma and adenoma. However, no further malignancies occurred in the extended follow-up evaluation of this drug until today. Vicriviroc is currently entering phase III evaluation. Pharmacokinetics of maraviroc and vicriviroc may be influenced by coadministration of CYP3A4-inhibitors and -inducers, since both substances are metabolised primarily by the CYP3A4 system. This requires dose adjustments when combined with for instance protease inhibitors (with the exception of tipranavir/r), efavirenz, ketoconazole or rifampin. Concerns have risen about possible class-specific long-term adverse effects of CCR5 antagonists, particularly with regard to hep

Topics: Anti-HIV Agents; Benzoates; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Diketopiperazines; Drug Interactions; Humans; Maraviroc; Piperazines; Pyrimidines; Spiro Compounds; Triazoles

A new class of antiretroviral drugs is now available to the HIV provider: The CCR5 Antagonists belong to a group of entry inhibitors with a novel mechanism of action. While these antagonists do not directly interfere with any of the steps of HIV replication, they block the CCR5 receptor, one of the co-receptors HIV uses to enter its target cell. Thus CCR5 antagonists are able to prevent infection of the cell and represent a new and unique mechanism for the treatment of HIV. There is great interest in utilizing this new drug class in early treatment of HIV to prevent infection of large cell pools; CCR5 antagonists even may be useful tools in the various settings of exposure prophylaxis. Maraviroc is now approved in both the European Union and the United States for the treatment of HIV infection. This is the first medication belonging to the new class of CCR5 antagonists, and the first approval of an orally available drug in a new class since 1996. Aplaviroc, maraviroc, and vicriviroc are small molecule inhibitors of CCR5 that block HIV-1 infection in vitro and reduce plasma HIV-1 RNA in HIV infected subjects by approximately 1.5 log10 copies/mL over 10-14 days when given as single agents. Very limited data is available on the use of CCR5 antagonists in treatment naive patients due to early termination of many trials because of inferior performance or toxicity and at the time of this writing in August 2007 there is only one ongoing non-inferiority trial in the naive patient population. The 48 week interim results of this trial using twice daily maraviroc were reported at the International AIDS Society meeting in July 2007. Maraviroc compared to efavirenz was non-inferior in regards to percentage of subjects reaching viral loads below 400 copies/mL, but not so for the analysis of subjects reaching viral loads below 50 copies/mL. On the other hand maraviroc had a superior side-effect profile, fewer adverse events and a greater increase of CD4 cell count than efavirenz. These data will revitalize the interest in CCR5 antagonists as a treatment option for the treatment-naive patients. In order to be used as first line drugs, CCR5 antagonists face a number of challenges: They will have to be proven to be as potent, durable, safe, and convenient as current available options. Important questions unique to this new class will have to be answered: What are the mechanisms and risks of tropism change? What is the role and needed frequency of tropism testing, and what

Topics: Adolescent; Adult; Anti-HIV Agents; Benzoates; CCR5 Receptor Antagonists; Cyclohexanes; Diketopiperazines; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; Middle Aged; Piperazines; Pyrimidines; Randomized Controlled Trials as Topic; Spiro Compounds; Triazoles

Topics: Benzoates; CCR5 Receptor Antagonists; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Cyclohexanes; Diketopiperazines; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Piperazines; Pyrimidines; Spiro Compounds; Treatment Outcome; Triazoles

In addition to being an important receptor in leukocyte activation and mobilization, CCR5 is the essential coreceptor for human immunodeficiency virus (HIV). A large number of small-molecule CCR5 antagonists have been reported that show potent activities in blocking chemokine function and HIV entry. To facilitate the design and development of next generation CCR5 antagonists, docking models for major classes of CCR5 antagonists were created by using site-directed mutagenesis and CCR5 homology modeling. Five clinical candidates: maraviroc, vicriviroc, aplaviroc, TAK-779, and TAK-220 were used to establish the nature of the binding pocket in CCR5. Although the five antagonists are very different in structure, shape, and electrostatic potential, they were able to fit in the same binding pocket formed by the transmembrane (TM) domains of CCR5. It is noteworthy that each antagonist displayed a unique interaction profile with amino acids lining the pocket. Except for TAK-779, all antagonists showed strong interaction with Glu283 in TM 7 via their central basic nitrogen. The fully mapped binding pocket of CCR5 is being used for structure-based design and lead optimization of novel anti-HIV CCR5 inhibitors with improved potency and better resistance profile.

Topics: Amides; Amino Acid Sequence; Animals; Anti-HIV Agents; Benzoates; Binding Sites; CCR5 Receptor Antagonists; CHO Cells; Cricetinae; Cricetulus; Cyclohexanes; Diketopiperazines; HIV Fusion Inhibitors; HIV-1; Humans; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Maraviroc; Membrane Fusion; Models, Molecular; Molecular Sequence Data; Molecular Structure; Mutagenesis, Site-Directed; Piperazines; Piperidines; Protein Structure, Secondary; Protein Structure, Tertiary; Pyrimidines; Quaternary Ammonium Compounds; Radioligand Assay; Receptors, CCR5; Sequence Homology, Amino Acid; Spiro Compounds; Static Electricity; Transfection; Triazoles

Inhibition of CCR5 co-receptor which is also a chemokine receptor, is a new way for inhibition of HIV-1 replication. Small antagonist molecules exert non competitive inhibition of the HIV co-receptor CCR5, which is essential for HIV entry. The CCR5 antagonists aplaviroc (GlaxoSmithKine), vicriviroc (Schering-Plough), and maraviroc (Pfizer) have reached phases III of clinical development. The development of aplaviroc was stopped because of its hepatotoxicity in some of the HIV-infected patients. In ACTG 5211 and MOTIVATE trials, treatment-experienced subjects who added respectively vicriviroc and maraviroc demonstrated substantially greater reductions in plasma HIV-1 RNA levels than those who received the placebo ; maraviroc currently having obtained European authorization. The place of this new class in the strategies of initial, switch or rescue treatment remains to be clarified. The limitations of the use of these small molecules depend on their mechanism of action : obligation for monitoring the evolution of coreceptor usage, risk of failure by emergence of pre-existing strains with CXCR4 (X4) tropism or by resistant strains with CCR5 tropism, potential risks related to blocking of the physiological functions of this chemokine receptor.

Topics: Benzoates; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Diketopiperazines; HIV Fusion Inhibitors; HIV Infections; Humans; Maraviroc; Piperazines; Pyrimidines; Spiro Compounds; Triazoles