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

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

doi:10.1016/j.bmcl.2011.12.117

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

Bioorg Med Chem Lett. 2012 Feb 15;22(4):1655-9. doi: 10.1016/j.bmcl.2011.12.117. Epub 2012 Jan 2.

Authors

John G Cumming¹, Howard Tucker, John Oldfield, Colin Fielding, Adrian Highton, Alan Faull, Martin Wild, Dearg Brown, Stuart Wells, John Shaw

Affiliation

¹ Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK. john.cumming@astrazeneca.com

PMID: 22266038
DOI: 10.1016/j.bmcl.2011.12.117

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.

MeSH terms

Absorption
Administration, Oral
Arthritis, Rheumatoid* / drug therapy
Benzeneacetamides / administration & dosage
Benzeneacetamides / chemical synthesis*
Benzeneacetamides / pharmacology
CCR5 Receptor Antagonists*
Drug Discovery*
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / chemistry
Ether-A-Go-Go Potassium Channels / metabolism*
Humans
Inhibitory Concentration 50
Molecular Structure
Protein Binding / drug effects
Receptors, CCR5 / metabolism
Sulfonamides / administration & dosage
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacology

Substances

Benzeneacetamides
CCR5 Receptor Antagonists
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
KCNH2 protein, human
N-(1-(3-(3,5-difluorophenyl)-3-(4-methanesulfonylphenyl)propyl)piperidin-4-yl)-N-ethyl-2-(4-methanesulfonylphenyl)acetamide
Receptors, CCR5
Sulfonamides