title: Some 3-(4-aminophenyl)pyrrolidine-2,5-diones as all-trans-retinoic acid metabolising enzyme inhibitors (RAMBAs).
abstract: A series of (+/-)-3-(4-aminophenyl) pyrrolidin-2,5-diones substituted in the 1-, 3- or 1,3-position with an aryl or long chain alkyl function are weak inhibitors of the metabolism of all-trans retinoic acid (RA) by rat liver microsomes (68-75% inhibition) compared with ketoconazole (85%). Further studies with the 1-cyclohexyl analogue (1) (IC50 = 98.8 microM, ketoconazole, 22.15 microM) showed that it was not stereoselective in its inhibition. (+/-)-(1) was not an inhibitor of pig brain microsomal enzyme (ketoconazole, IC50 = 20.9 microM), had little effect on human liver microsomal enzyme (19.3%, ketoconazole, 81.6%) or human placental microsomal enzyme (9.8%, ketoconazole 73.9%) but was a weak inhibitor of human and rat skin homogenates (52.6% and IC50 = 211.6 microM respectively; ketoconazole, 38.8% and 85.95 microM). In RA-induced cell cultures of human male genital fibroblasts and HaCat cells, (+/-)-(1) was a weak inhibitor (c. 53% at 200 microM) whereas ketoconazole showed high potency (c. 65% at 0.625 microM and 0.25 microM respectively). The nature of the induced target enzyme is discussed.
authors.affiliation: Pharmacology Division, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kirby
authors.forename: Regis
authors.initials: R
authors.lastname: Lelain
authors.forename: Peter
authors.initials: P
authors.lastname: Mason
authors.forename: Farshid
authors.initials: F
authors.lastname: Maharlouie
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Nicholls
authors.forename: H John
authors.initials: HJ
authors.lastname: Smith
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D001940:Breast / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D010920:Placenta / Q000201:enzymology / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000201:enzymology / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D014212:Tretinoin