title: Small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26): synthesis and biological evaluation of imidazole methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates.
abstract: The synthesis and potent inhibitory activity of novel imidazole methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates in a MCF-7 CYP26A1 microsomal assay is described. The induction of CYP26A1 mRNA was used to evaluate the ability of the compounds to enhance the biological effects of all-trans retinoic acid (ATRA) in a retinoid-responsive neuroblastoma cell line. The most promising inhibitor, 3-imidazol-1-yl-2-methyl-3-[4-(naphthalen-2-ylamino)-phenyl]-propionic acid methyl ester (20), with an IC(50) of 3 nM (compared with liarozole IC(50) of 540 nM and R116010 IC(50) of 10 nM) was further evaluated for CYP selectivity using a panel of CYP enzymes, mutagenicity (Ames screen), and hepatic stability.
authors.affiliation: Medicinal Chemistry Division, Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Gomaa
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Bridgens
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Aboraia
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
authors.forename: Christopher P F
authors.initials: CP
authors.lastname: Redfern
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Jane L
authors.initials: JL
authors.lastname: Armstrong
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
mesh_terms: D045744:Cell Line, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011407:Propane / Q000031:analogs & derivatives*; D012333:RNA, Messenger / Q000235:genetics; D000072516:Retinoic Acid 4-Hydroxylase; D013237:Stereoisomerism
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D011407:Propane