Antagonist maraviroc

Westby M, Smith-Burchnell C, Mori J, Lewis M, Mosley M, Stockdale M, Dorr P, Ciaramella G, Perros M (2007) Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry, J Virol 81 2359-2371... 

In the discovery of the CCR5 antagonist maraviroc, Price et al. [14] were able to generate high selectivity over hERG. Docking of compounds from the series... 

Figure 1.7 Elimination of hERG activity in the design of the CCR5 antagonist, maraviroc.

Price, D.A., et al. Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc. Bioorg. Med. Chem. Lett. 2006, 16, 4633-4637. 

Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005 11(11) 1170-1172. 

The development of maraviroc (21), much like other chemokine receptor antagonists, started with a high-throughput screen employing a competition binding assay and led to the hit compound UK-107,543. Chemical optimization of this compound led to the development candidate UK-427,857 during this optimization phase, a parallel characterization of the compounds was performed... 

Fig. 4. Structure of UK-427,857 (maraviroc), a CCR5-specific antagonist from Pfizer currently in phase III studies for HIV treatment. The original hit from the high-throughput screening, compound UK107,543, is also shown.

Maraviroc (Selzentry) The First-in-Class CCR5 Antagonist for the... 

Selzentry (maraviroc, MVC, UK-427,857) which functions as a CCR5 coreceptor antagonist.7... 

Scheme 7.3 Synthesis of Maraviroc (10), an antagonist of the CCR5 receptor.

CCR5 antagonists are a new class of entry inhibitors currently under development. Maraviroc is the nearest to marketing, and is a substrate of CYP3A4. Because of this, CYP3A4 inducers (e.g. efavirenz) lower its levels and CYP3A4 inhibitors (e.g. protease inhibitors) increase its levels. 

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