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

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 = 1 nM, IC50 = 1.3 nM; CXCR1 Ki = 3 nM, IC50 = 7.3 nM), and demonstrates potent inhibition against both Gro-α and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC50 = 0.5 nM, CXCR1 IC50 = 37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog.

The discovery and synthesis of the potent CXCR2 and CXCR1 dual antagonist 16 is described.Figure optionsDownload as PowerPoint slide