CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity

  • Bioorg Med Chem Lett. 2007 Jun 1;17(11):2992-7. doi: 10.1016/j.bmcl.2007.03.065.
James R Pruitt  1 ,  Douglas G Batt ,  Dean A Wacker ,  Lori L Bostrom ,  Shon K Booker ,  Erin McLaughlin ,  Gregory C Houghton ,  Jeffrey G Varnes ,  David D Christ ,  Maryanne Covington ,  Anuk M Das ,  Paul Davies ,  Danielle Graden ,  Ilona Kariv ,  Yevgeniya Orlovsky ,  Nicole C Stowell ,  Krishna G Vaddi ,  Eric A Wadman ,  Patricia K Welch ,  Swamy Yeleswaram ,  Kimberly A Solomon ,  Robert C Newton ,  Carl P Decicco ,  Percy H Carter ,  Soo S Ko
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA.
PMID: 17418570 DOI: 10.1016/j.bmcl.2007.03.065
Abstract

DPC168, a benzylpiperidine-substituted aryl urea CCR3 Antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.

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