title: Synthesis and CYP26A1 inhibitory activity of novel methyl 3-[4-(arylamino)phenyl]-3-(azole)-2,2-dimethylpropanoates.
abstract: The role of all-trans-retinoic acid (ATRA) in the development and maintenance of many epithelial and neural tissues has raised great interest in the potential of ATRA and related compounds (retinoids) as pharmacological agents, particularly for the treatment of cancer, skin, neurodegenerative and autoimmune diseases. The use of ATRA or prodrugs as pharmacological agents is limited by a short half-life in vivo resulting from the activity of specific ATRA hydroxylases, CYP26 enzymes, induced by ATRA in liver and target tissues. For this reason retinoic acid metabolism blocking agents (RAMBAs) have been developed for treating cancer and a wide range of other diseases. The synthesis, CYP26A1 inhibitory activity and molecular modeling studies of novel methyl 3-[4-(arylamino)phenyl]-3-(azole)-2,2-dimethylpropanoates are presented. From this series of compounds clear SAR can be derived for 4-substitution of the phenyl ring with electron-donating groups more favourable for inhibitory activity. Both the methylenedioxyphenyl imidazole (17, IC(50) = 8 nM) and triazole (18, IC(50) = 6.7 nM) derivatives were potent inhibitors with additional binding interactions between the methylenedioxy moiety and the CYP26 active site likely to be the main factor. The 6-bromo-3-pyridine imidazole 15 (IC(50) = 5.7 nM) was the most active from this series compared with the standards liarozole (IC(50) = 540 nM) and R116010 (IC(50) = 10 nM).
authors.affiliation: Medicinal Chemistry Division, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Gomaa
authors.forename: Andrew S T
authors.initials: AS
authors.lastname: Lim
authors.forename: S C Wilson
authors.initials: SC
authors.lastname: Lau
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Watts
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Illingworth
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: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001393:Azoles / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007093:Imidazoles; D061986:MCF-7 Cells; D008861:Microsomes / Q000378:metabolism; D062105:Molecular Docking Simulation; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000072516:Retinoic Acid 4-Hydroxylase; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry
chemical_list: D000631:Aminopyridines; D001393:Azoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D010666:Phenylpropionates; D011422:Propionates; D014230:Triazoles; C578259:methyl 3-(4-(6-bromopyridin-3-ylamino)phenyl)-3-(1H-imidazol-1-yl)-2,2-dimethylpropanoate; D014212:Tretinoin; C029899:imidazole; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase