title: Arylacetamide kappa opioid receptor agonists with reduced cytochrome P450 2D6 inhibitory activity.
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.
authors.affiliation: Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. blebourdonnec@adolor.com
authors.forename: Bertrand
authors.initials: B
authors.lastname: Le Bourdonnec
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ajello
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Seida
authors.forename: Roberta G
authors.initials: RG
authors.lastname: Susnow
authors.forename: Joel A
authors.initials: JA
authors.lastname: Cassel
authors.forename: Serge
authors.initials: S
authors.lastname: Belanger
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Stabley
authors.forename: Robert N
authors.initials: RN
authors.lastname: DeHaven
authors.forename: Diane L
authors.initials: DL
authors.lastname: DeHaven-Hudkins
authors.forename: Roland E
authors.initials: RE
authors.lastname: Dolle
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013379:Substrate Specificity
chemical_list: D000081:Acetamides; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D017473:Receptors, Opioid, kappa; C030686:acetamide