10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 12
P. Dorr, M. Macartney, G. Rickett, C. Smith-Burchnell, S. Dobbs, J. Mori, P. Griffin, J. Lok, R. Irvine, M. Westby, C. Hitchcock , B. Stammen, D. Price, D. Armour, A. Wood, M. Perros
Pfizer Global R&D, Sandwich Labs, Kent, UK

BACKGROUND: Compounds that prevent the binding and fusion of HIV to its target cells have recently shown clinical efficacy, paving the path for a new class of antiretroviral agents. The HIV co-receptor CCR5 is a particularly attractive target for the discovery of viral entry inhibitors, as G-protein coupled receptors have traditionally proven tractable targets for the design of selective, low-dose orally bioavailable drugs.

METHODS: UK-427,857, our prototype clinical development candidate for HIV infection, is the product of a high-throughput screening approach and subsequent medicinal chemistry optimisation. We measured the activity of UK-427,857 against both primary and lab-adapted viral isolates in vitro, using p24 and RT activity as readouts. We also applied a range of biological and physicochemical assays to characterise the activity of UK-427,857 both in respect to viral replication and to cognate chemokine binding and receptor function.

RESULTS: UK-427,857 has excellent potency against a range of lab-adapted and primary origin isolates that utilise CCR5 for entry (IC₉₀ < 10 nM against 43 isolates from clades A-G, J, and O in PBMCs). UK-427,857 is inactive against CXCR4-tropic viral isolates, consistent with the expected mechanism of action. Using in vitro models, we have shown that the inhibitor blocks viral replication at the point of membrane fusion (IC₅₀ = 0.2 nM), by preventing the binding of the viral envelope gp120 to the co-receptor CCR5 (IC₅₀ = 43 nM). UK-427,857 obliterates cognate chemokine ligand binding (Mip1βIC₅₀ = 3 - 7nM) with exquisite specificity. Studies that include intracellular Ca⁺⁺ ion redistribution, cytofluorimetry, and γS-GTP labelling demonstrate that UK-427,857 does not induce intracellular signalling or trigger receptor internalisation. We have also shown that UK-427,857 is non-competitive with regards to chemokine binding, and binds the receptor reversibly albeit with a long half-life. Amongst other potential advantages, this profile opens the interesting perspective of advantageous pharmacodynamics.

CONCLUSIONS: UK-427,857 is a prototype CCR5 antagonist for the treatment of HIV infection, with excellent potency against lab-adapted and primary strains. The predicted pharmacokinetic and safety profile of the candidate are such that the compound has the potential to block receptor binding akin to the naturally protective Δ32-CCR5 homozygous phenotype, when administered to humans with one or more wt-CCR5 alleles.

030210
12

Copyright © 2003 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.