ABSTRACT
High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Drug Discovery , Piperidines/pharmacology , Receptors, CCR1/antagonists & inhibitors , Urea/analogs & derivatives , Valine/analogs & derivatives , Animals , Biological Availability , Clinical Trials, Phase II as Topic , Hep G2 Cells , Humans , Male , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/metabolism , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Pregnane X Receptor , Protein Conformation , Receptors, CCR1/chemistry , Receptors, CCR1/metabolism , Receptors, Steroid/metabolism , Species Specificity , Urea/metabolism , Urea/pharmacokinetics , Urea/pharmacology , Urea/therapeutic use , Valine/metabolism , Valine/pharmacokinetics , Valine/pharmacology , Valine/therapeutic useABSTRACT
A series of compounds which exhibited good human CCR1 binding and functional potency was modified resulting in the discovery of a novel series of high affinity, functionally potent antagonists of the CCR1 receptor. Issues of PXR activity, ion-channel potency, and poor metabolic stability were addressed by the addition of a hydroxyl group to an otherwise lipophilic area in the molecule resulting in the discovery of preclinical candidate BMS-457 for the treatment of rheumatoid arthritis.
