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.
Subject(s)
Arthritis, Rheumatoid , Benzeneacetamides/chemical synthesis , CCR5 Receptor Antagonists , Drug Discovery , Ether-A-Go-Go Potassium Channels/metabolism , Sulfonamides/chemical synthesis , Absorption , Administration, Oral , Arthritis, Rheumatoid/drug therapy , Benzeneacetamides/administration & dosage , Benzeneacetamides/pharmacology , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Binding/drug effects , Receptors, CCR5/metabolism , Sulfonamides/administration & dosage , Sulfonamides/pharmacologyABSTRACT
SAR and PK studies led to the identification of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl] propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide as a highly potent and selective ligand for the human CCR5 chemokine receptor with good oral pharmacokinetic properties.
Subject(s)
Acetanilides/chemistry , Acetanilides/pharmacokinetics , CCR5 Receptor Antagonists , Piperidines/chemistry , Piperidines/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , Acetanilides/chemical synthesis , Animals , Crystallography, X-Ray , Dogs , Humans , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Rats , Stereoisomerism , Structure-Activity Relationship , Sulfones/chemical synthesis , Time FactorsABSTRACT
SAR and DMPK studies led to the identification of substituted N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides as potent and orally bioavailable ligands for the human CCR5 chemokine receptor.
