title: Potent CYP19 (aromatase) 1-[(benzofuran-2-yl)(phenylmethyl)pyridine, -imidazole, and -triazole inhibitors: synthesis and biological evaluation.
abstract: The synthesis of a series of novel 1-[(benzofuran-2-yl)phenylmethyl]-pyridine, -imidazole, and -triazole derivatives is described. All the compounds were evaluated in vitro for inhibitory activity against aromatase (P450(AROM), CYP19), using human placental microsomes. The 6-methoxy- and 6-hydroxy-substituted benzofuran derivatives were shown to be potent CYP19 inhibitors (IC(50) = 0.01-1.46 microM) with activity greater than that observed for the unsubstituted parent compounds and inhibitory activity comparable with or greater than the reference compound arimidex (IC(50) = 0.6 microM). Six of the benzofuran derivatives were subjected to in vitro cytotoxicity assays, using rat liver hepatocytes with cytotoxicity determined from alteration in cell morphology and lactate dehydrogenase enzyme retention over a period of 24 h, and selectivity (CYP17, 17beta-HSD types 1 and 3, CYP24, and CYP26) determination; negligible inhibitory activity was observed, suggesting a good selectivity for CYP19. The pyridine benzofuran 4a containing the 4-fluorophenyl group was the most promising (IC(50) = 44 nM; LC(50) >100 microM) compared with arimidex (IC(50) = 600 nM; LC(50) > 200 microM).
authors.affiliation: Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, Wales, U.K.
authors.forename: Mohammed Reza
authors.initials: MR
authors.lastname: Saberi
authors.forename: Tai Ky
authors.initials: TK
authors.lastname: Vinh
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.forename: B J Nathan
authors.initials: BJ
authors.lastname: Griffiths
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Evans
authors.forename: Claire
authors.initials: C
authors.lastname: Simons
mesh_terms: D000818:Animals; D001141:Aromatase / Q000737:chemistry / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D010920:Placenta / Q000201:enzymology / Q000648:ultrastructure; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
chemical_list: C508993:6-methoxybenzofuran-2-yl-(4-fluorophenyl)-3-pyridylmethanol; D047072:Aromatase Inhibitors; D001572:Benzofurans; D007093:Imidazoles; D011725:Pyridines; D014230:Triazoles; D007770:L-Lactate Dehydrogenase; D001141:Aromatase