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

  • Bioorg Med Chem Lett. 2007 Jul 1;17(13):3778-83. doi: 10.1016/j.bmcl.2007.04.016.
Jianhua Chao " href="affiliation-1" ref="linksrc=author_aff">  #  1 ,  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
Affiliations
  • 1. Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. [email protected]
  • # Contributed equally.
PMID: 17459706 DOI: 10.1016/j.bmcl.2007.04.016
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.

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