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The Discovery of the CCR5 Receptor Antagonist, UK-427,857, A New Agent for the Treatment of HIV Infection and AIDS

2005; Elsevier BV; Linguagem: Inglês

10.1016/s0079-6468(05)43007-6

1875-7863

Anthony Wood, Duncan Armour,

Monoclonal and Polyclonal Antibodies Research

The CCR5 receptor is a member of the family of G-protein coupled receptors and is predicted to have a typical seven transmembrane structure. This class of proteins is heavily represented in the druggable genome, which gives some encouragement that a drug-like ligand should be identifiable. This chapter describes the drug discovery program that led to the identification of UK-427,857, a prototype CCR5 antagonist with excellent potency against lab-adapted and primary HIV-1 isolates, as a clinical candidate for the treatment of HIV. UK-427,857 (54) possessed excellent antiviral potency and reasonable microsomal stability combined with good selectivity over potential ion channel effects. The potency of UK-427,857 (54) was encouraging when tested against HIVBaL in peripheral blood monocytes where the receptor is expressed under its native conformations (IC 90 = 6 nM) but was even more exciting when extensively tested against primary origin HIV isolates. The chapter also deals with the strategies for minimizing cardiac toxicity, while maintaining ADME properties commensurate with low dose.