C(4)-alkyl substituted furanyl cyclobutenediones as potent, orally bioavailable CXCR2 and CXCR1 receptor antagonists.
Jianhua Chao, Arthur G Taveras, Jianping Chao, Cynthia Aki, Michael Dwyer, Younong Yu, Biju Purakkattle, Diane Rindgen, James Jakway, William Hipkin, James Fosetta, Xuedong Fan, Daniel Lundell, Jay Fine, Michael Minnicozzi, Jonathan Phillips, J Robert Merritt
Index: Bioorg. Med. Chem. Lett. 17 , 3778, (2007)
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Abstract
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, IC(50)=1.3 nM; CXCR1 Ki=3 nM, IC(50)=7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5 nM, CXCR1 IC(50)=37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog.