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Antimicrobial Agents and Chemotherapy, November 2005, p. 4721-4732, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4721-4732.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Patrick Dorr,* Mike Westby, Susan Dobbs, Paul Griffin, Becky Irvine, Malcolm Macartney, Julie Mori, Graham Rickett, Caroline Smith-Burchnell, Carolyn Napier, Rob Webster, Duncan Armour, David Price, Blanda Stammen, Anthony Wood, and Manos Perros

Pfizer Global Research and Development-Sandwich Laboratories, Sandwich, Kent CT13 9NJ, United Kingdom

Received 22 February 2005/ Returned for modification 10 May 2005/ Accepted 21 July 2005

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 µM), 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.

* Corresponding author. Mailing address: Discovery Biology, Pfizer GRD-Sandwich Laboratories, Kent CT13 9NJ, United Kingdom. Phone: 44 (0)1304 616161. Fax: 44 (0)1304 651819. E-mail: patrick.dorr{at}pfizer.com.

Antimicrobial Agents and Chemotherapy, November 2005, p. 4721-4732, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4721-4732.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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