Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency

  • J Med Chem. 2005 Mar 24;48(6):2194-211. doi: 10.1021/jm049530m.
George V De Lucca  1 ,  Ui Tae Kim ,  Brian J Vargo ,  John V Duncia ,  Joseph B Santella 3rd ,  Daniel S Gardner ,  Changsheng Zheng ,  Ann Liauw ,  Zhang Wang ,  George Emmett ,  Dean A Wacker ,  Patricia K Welch ,  Maryanne Covington ,  Nicole C Stowell ,  Eric A Wadman ,  Anuk M Das ,  Paul Davies ,  Swamy Yeleswaram ,  Danielle M Graden ,  Kimberly A Solomon ,  Robert C Newton ,  George L Trainor ,  Carl P Decicco ,  Soo S Ko
Affiliations
  • 1. Bristol-Myers Squibb Company, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. [email protected]
PMID: 15771462 DOI: 10.1021/jm049530m
Abstract

Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the Lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.