title: Synthesis and biological evaluation of 3-(1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-[4-(naphthalen-2-ylamino)phenyl]propyl derivatives as small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26).
abstract: The synthesis and potent inhibitory activity of novel 3-(1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-(4-(naphthalen-2-ylamino)phenyl)propyl derivatives vs a MCF-7 CYP26A1 microsomal assay is described. This study focused on the effect of modifying the heme binding azole group and the flexible C3 chain on inhibitory activity and selectivity. The most promising inhibitor 2,2-dimethyl-3-[4-(naphthalen-2-ylamino)-phenyl]-3-[1,2,4]triazol-1-yl-propionic acid methyl ester (17) (IC(50) = 0.35 nM as compared with liarozole IC(50) = 540 nM and R116010 IC(50) = 10 nM) was evaluated for CYP selectivity and hepatic stability. Compounds with CYP26 inhibitory IC(50) values ≤50 nM enhanced the biological activity of exogenous ATRA, as evidenced by a 3.7-5.8-fold increase in CYP26A1 mRNA in SH-SY5Y neuroblastoma cells as compared with ATRA alone. All compounds demonstrated an activity comparable with or better than R116010, and the induction correlated well with CYP26 inhibition data. These studies highlight the promising activity profile of this novel CYP26 inhibitor and suggest it as an appropriate candidate for future development.
authors.affiliation: Medicinal Chemistry Division, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Gomaa
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Bridgens
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: D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C568513:2,2-dimethyl-3-(4-(naphthalen-2-ylamino)phenyl)-3-(1,2,4)triazol-1-yl-propionic acid methyl ester; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D009281:Naphthalenes; D012333:RNA, Messenger; D014230:Triazoles; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D015081:2-Naphthylamine; D000072516:Retinoic Acid 4-Hydroxylase