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.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Jagusch C,Negri M,Hille UE,Hu Q,Bartels M,Jahn-Hoffmann K,Pinto-Bazurco Mendieta MA,Rodenwaldt B,Müller-Vieira U,Schmidt D,Lauterbach T,Recanatini M,Cavalli A,Hartmann RWdoi
10.1016/j.bmc.2007.10.094subject
Has Abstractpub_date
2008-02-15 00:00:00pages
1992-2010issue
4eissn
0968-0896issn
1464-3391pii
S0968-0896(07)00960-1journal_volume
16pub_type
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