Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure.

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Citation

Jagusch C, Negri M, Hille UE, Hu Q, Bartels M, Jahn-Hoffmann K, Pinto-Bazurco Mendieta MA, Rodenwaldt B, Muller-Vieira U, Schmidt D, Lauterbach T, Recanatini M, Cavalli A, Hartmann RW

Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure.

Bioorg Med Chem. 2008 Feb 15;16(4):1992-2010. Epub 2007 Nov 4.

PubMed ID
18061460 [ View in PubMed
]
Abstract

Novel chemical entities were prepared via Suzuki and S(N) reaction as AC-ring substrate mimetics of CYP17. The synthesised compounds 1-31 were tested for activity using human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against hepatic CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, 2B6). Two potent inhibitors (27, IC50 = 373 nM/28, IC50 = 953 nM) were further examined in rats regarding their effects on plasma testosterone levels and their pharmacokinetic properties. Compound 28 was similarly active as abiraterone and showed better pharmacokinetic properties (higher bioavailability, t(1/2) 9.5 h vs 1.6 h). Docking studies revealed two new binding modes different from the one of the substrates and steroidal inhibitors.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AbirateroneSteroid 17-alpha-hydroxylase/17,20 lyaseIC 50 (nM)72N/AN/ADetails