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Overcoming hERG Affinity in the Discovery of Maraviroc; A CCR5 Antagonist for the Treatment of HIV

[ Vol. 8 , Issue. 13 ]


David A. Price, Duncan Armour, Marcel de Groot, Derek Leishman, Carolyn Napier, Manos Perros, Blanda L. Stammen and Anthony Wood   Pages 1140 - 1151 ( 12 )


Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.


Maraviroc, Antagonist, Treatment of HIV, blockade, hydrophobic interactions, lipophilicity


Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc., Eastern Point Road, Groton, USA. CT 06340.

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