1. CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity.
- Author
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Pruitt JR, Batt DG, Wacker DA, Bostrom LL, Booker SK, McLaughlin E, Houghton GC, Varnes JG, Christ DD, Covington M, Das AM, Davies P, Graden D, Kariv I, Orlovsky Y, Stowell NC, Vaddi KG, Wadman EA, Welch PK, Yeleswaram S, Solomon KA, Newton RC, Decicco CP, Carter PH, and Ko SS
- Subjects
- Animals, Benzyl Compounds chemical synthesis, Biological Assay, Cells, Cultured, Humans, Mice, Pan troglodytes, Phenylurea Compounds pharmacology, Piperidines chemical synthesis, Receptors, CCR3, Structure-Activity Relationship, Benzyl Compounds chemistry, Benzyl Compounds pharmacology, Cytochrome P-450 CYP2D6 Inhibitors, Phenylurea Compounds chemistry, Piperidines chemistry, Piperidines pharmacology, Receptors, Chemokine antagonists & inhibitors
- 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.
- Published
- 2007
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