RESUMO
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.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Descoberta de Drogas , Piperidinas/farmacologia , Receptores CCR1/antagonistas & inibidores , Ureia/análogos & derivados , Valina/análogos & derivados , Animais , Disponibilidade Biológica , Ensaios Clínicos Fase II como Assunto , Células Hep G2 , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/metabolismo , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Receptor de Pregnano X , Conformação Proteica , Receptores CCR1/química , Receptores CCR1/metabolismo , Receptores de Esteroides/metabolismo , Especificidade da Espécie , Ureia/metabolismo , Ureia/farmacocinética , Ureia/farmacologia , Ureia/uso terapêutico , Valina/metabolismo , Valina/farmacocinética , Valina/farmacologia , Valina/uso terapêuticoRESUMO
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.