RESUMO
A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1-expressing cell line. A potent, optimized triazole lead from this series was found to have acceptable pharmacokinetics and microsomal stability in rat and is suitable for further optimization and development.
Assuntos
Quimiocina CCL3/imunologia , Quimiotaxia/efeitos dos fármacos , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores CCR1/antagonistas & inibidores , Animais , Linhagem Celular , Microssomos Hepáticos/metabolismo , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Ratos , Receptores CCR1/imunologia , Triazóis/química , Triazóis/metabolismo , Triazóis/farmacocinética , Triazóis/farmacologiaRESUMO
Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1alpha (MIP-1alpha) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC(50) of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.
