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

• Published in: Bioorganic & medicinal chemistry letters 2007-07, Vol.17 (13), p.3778-3783
• Main Authors: Chao, Jianhua, Taveras, Arthur G., Chao, Jianping, Aki, Cynthia, Dwyer, Michael, Yu, Younong, Purakkattle, Biju, Rindgen, Diane, Jakway, James, Hipkin, William, Fosetta, James, Fan, Xuedong, Lundell, Daniel, Fine, Jay, Minnicozzi, Michael, Phillips, Jonathan, Merritt, J. Robert
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Area Under Curve; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Pharmaceutical - methods; CXCR1 receptor; CXCR2 receptor; Dogs; Drug Design; Dual antagonists; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacokinetics; Humans; Inhibitory Concentration 50; Interleukin-8 - chemistry; Kinetics; Medical sciences; Mice; Pharmacology. Drug treatments; Rats; Receptors, Interleukin-8A - antagonists & inhibitors; Receptors, Interleukin-8B - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.04.016

The discovery and synthesis of the potent CXCR2 and CXCR1 dual antagonist 16 is described. 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-α 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.