Arylacetamide kappa opioid receptor agonists with reduced cytochrome P450 2D6 inhibitory activity |
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Authors: | Le Bourdonnec Bertrand Ajello Christopher W Seida Pamela R Susnow Roberta G Cassel Joel A Belanger Serge Stabley Gabriel J DeHaven Robert N DeHaven-Hudkins Diane L Dolle Roland E |
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Affiliation: | Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. blebourdonnec@adolor.com |
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Abstract: | Some kappa opioid receptor agonists of the arylacetamide class, for example, ICI 199441 (1), were found to strongly inhibit the activity of cytochrome P450 2D6 (CYP2D6) (1: CYP2D6 IC50=26 nM). Certain analogs bearing a substituted sulfonylamino group, for example, 13, were discovered to have significantly reduced CYP2D6 inhibitory activity (13: CYP2D6 IC50>10 microM) while displaying high affinity toward the cloned human kappa opioid receptor, good kappa/delta and kappa/mu selectivity, and potent in vitro and in vivo agonist activity. |
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