C(4)-alkyl substituted furanyl cyclobutenediones as potent, orally bioavailable CXCR2 and CXCR1 receptor antagonists.

摘要

A novel series of cyclobutenedione centered C(4)-alkyl substituted furanyl analogs was developed as potent CXCR2 and CXCR1 antagonists. Compound 16 exhibits potent inhibitory activities against IL-8 binding to the receptors (CXCR2 Ki=1nM, IC(50)=1.3nM; CXCR1 Ki=3nM, IC(50)=7.3nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5nM, CXCR1 IC(50)=37nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog.