title: 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.
authors.affiliation: Discovery Biology, Pfizer Global Research and Development-Sandwich Laboratories, Kent CT13 9NJ, United Kingdom. patrick.dorr@pfizer.com
authors.forename: Patrick
authors.initials: P
authors.lastname: Dorr
authors.forename: Mike
authors.initials: M
authors.lastname: Westby
authors.forename: Susan
authors.initials: S
authors.lastname: Dobbs
authors.forename: Paul
authors.initials: P
authors.lastname: Griffin
authors.forename: Becky
authors.initials: B
authors.lastname: Irvine
authors.forename: Malcolm
authors.initials: M
authors.lastname: Macartney
authors.forename: Julie
authors.initials: J
authors.lastname: Mori
authors.forename: Graham
authors.initials: G
authors.lastname: Rickett
authors.forename: Caroline
authors.initials: C
authors.lastname: Smith-Burchnell
authors.forename: Carolyn
authors.initials: C
authors.lastname: Napier
authors.forename: Rob
authors.initials: R
authors.lastname: Webster
authors.forename: Duncan
authors.initials: D
authors.lastname: Armour
authors.forename: David
authors.initials: D
authors.lastname: Price
authors.forename: Blanda
authors.initials: B
authors.lastname: Stammen
authors.forename: Anthony
authors.initials: A
authors.lastname: Wood
authors.forename: Manos
authors.initials: M
authors.lastname: Perros
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008561:Membrane Fusion / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019713:Receptors, CCR5 / Q000378:metabolism; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc