Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity

Abstract

Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 microM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS.

FIG. 1.

Discovery of maraviroc from the high-throughput screening hit UK-107,453.

FIG. 2.

Effects of maraviroc on CCR5-mediated signaling. a: Maraviroc-dependent inhibition of RANTES-induced calcium redistribution. Fluorescence was measured in real time by FLIPR following addition of maraviroc and subsequent addition of 20 nM RANTES (both marked). b: effect of maraviroc on 300.19 cell surface CCR5 levels (anti-CCR5 antibody-dependent cell population fluorescence). Isotype control fluorescence is depicted in gray. RANTES (100 nM)-induced reduction of CCR5 is shown by a reduction in fluorescence [green line in panel b(i)] relative to parallel experiments using the negative control ligand SDF-1α [red line in panel b(i)]. Reemergence of CCR5 at the cell surface was apparent following a 2-h incubation period after addition of RANTES [blue line in panel b(i)]. RANTES-induced reduction in cell population fluorescence was reduced at 4°C [panel b(ii)], highlighting internalization to be an active biological process. Maraviroc did not affect cell population fluorescence at 10 nM or 100 nM [blue and green lines, respectively; panel b(iii)], as also seen for the negative control SDF-1α (red line).

FIG. 3.

Maraviroc-dependent inhibition of gp120 binding to CCR5 (red) and gp160-CCR5-mediated cell-cell fusion (black). Each data point represents the mean percent inhibition (relative to vehicle control) ± the standard error of the mean (bars).

FIG. 4.

Representative dose response for maraviroc-dependent inhibition of HIV strain Ba-L replication in pooled isolated peripheral blood lymphocytes (blue line and data points) compared to that with RANTES (red line and data points). Maraviroc yielded a geometric mean IC₅₀ of 0.56 nM (95% CI, 0.36 to 0.9 nM; n = 33) and RANTES a value of 2.2 nM (95% CI, 1.7 to 2.8 nM; n = 14). Data points represent the mean percent inhibition ± standard error of the mean for a representative assay.

FIG. 5.

Activity of maraviroc against a panel of 200 Env-recombinant pseudoviruses derived from clinical HIV-1, showing the n-fold change in IC₅₀ relative to that for strain JR-CSF for envelopes derived from normal and drug-resistant strains.