Potent CYP19 (aromatase) 1-[(benzofuran-2-yl)(phenylmethyl)pyridine, -imidazole, and -triazole inhibitors: synthesis and biological evaluation.
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).
Saberi
Mohammed Reza
MR
Medicinal Chemistry, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, Wales, U.K.
Vinh
Tai Ky
TK
Yee
Sook Wah
SW
Griffiths
B J Nathan
BJ
Evans
Peter J
PJ
Simons
Claire
C
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
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