title: Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis.
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.
authors.affiliation: Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK. john.cumming@astrazeneca.com
authors.forename: John G
authors.initials: JG
authors.lastname: Cumming
authors.forename: Howard
authors.initials: H
authors.lastname: Tucker
authors.forename: John
authors.initials: J
authors.lastname: Oldfield
authors.forename: Colin
authors.initials: C
authors.lastname: Fielding
authors.forename: Adrian
authors.initials: A
authors.lastname: Highton
authors.forename: Alan
authors.initials: A
authors.lastname: Faull
authors.forename: Martin
authors.initials: M
authors.lastname: Wild
authors.forename: Dearg
authors.initials: D
authors.lastname: Brown
authors.forename: Stuart
authors.initials: S
authors.lastname: Wells
authors.forename: John
authors.initials: J
authors.lastname: Shaw
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D044482:Benzeneacetamides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D019713:Receptors, CCR5 / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D044482:Benzeneacetamides; D065100:CCR5 Receptor Antagonists; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C553747:N-(1-(3-(3,5-difluorophenyl)-3-(4-methanesulfonylphenyl)propyl)piperidin-4-yl)-N-ethyl-2-(4-methanesulfonylphenyl)acetamide; D019713:Receptors, CCR5; D013449:Sulfonamides