CCR5 hERG problem

The GPCR receptors CCR5 and CCR4 are recognised on the surface of host T-cells by HIV virus particles. It was found that a group of the population had a mutation so their CCR5 receptors were not recognised and so did not get infected. This attractive target was tackled by many organisations and nearly all of them found similar chemical matter in the form of a bi-aryl group linked to a basic nitrogen. As these programs continued they coincided with the requirement for NCE to avoid (or be free of) any binding to the human ether a-go-go related gene product (aka hERG) ion-channel. The Pfizer research program had to optimise against this binding as well as bio-availability and in-vitro and in-vivo reduction of viral load.

Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc.

Bioorg. & Med. Chem. Lett. 2006, 16, 4633-4637.


Further hERG references:

Medicinal Chemistry of hERG Optimizations:  Highlights and Hang-Ups

J. Med. Chem. 2006, 49, 17, 5029–5046

hERG Me Out

J. Chem. Inf. Model. 2013, 53, 9, 2240–2251

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