Referenced in: none

Automatically associated channels: Kv11.1

Title: Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis.

Authors: John G Cumming, Howard Tucker, John Oldfield, Colin Fielding, Adrian Highton, Alan Faull, Martin Wild, Dearg Brown, Stuart Wells, John Shaw

Journal, date & volume: Bioorg. Med. Chem. Lett., 2012 Feb 15 , 22, 1655-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22266038

Abstract
Modifications to a series of potent and selective substituted 1-(3,3-diphenylpropyl)-piperidine phenylacetamide CCR5 antagonists were explored with the aim of reducing affinity at the hERG cardiac ion channel. Replacement of one aromatic ring in the diphenylpropyl region with less lipophilic, saturated heterocyclic rings and subsequent optimisation of the other phenyl ring led to the identification of clinical compound AZD5672 which retained excellent potency while reducing hERG affinity. Modulating lipophilicity affected the interplay between potency, hERG affinity and absorption. AZD5672 was found to have an acceptable balance of these properties and was progressed to a phase II clinical trial to test the hypothesis that inhibition of CCR5 will bring benefits in the treatment of rheumatoid arthritis.