Record number :
1304048
Title of article :
Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure Original Research Article
Author/Authors :
Carsten Jagusch، نويسنده , , Matthias Negri، نويسنده , , Ulrike E. Hille، نويسنده , , Qingzhong Hu، نويسنده , , Marc Bartels، نويسنده , , Kerstin Jahn-Hoffmann، نويسنده , , Mariano A.E. Pinto-Bazurco Mendieta، نويسنده , , Barbara Rodenwaldt، نويسنده , , Ursula Müller-Vieira، نويسنده , , Dirk Schmidt، نويسنده , , Thomas Lauterbach، نويسنده , , Maurizio Recanatini، نويسنده , , Andrea Cavalli and Michele Vendruscolo، نويسنده , , Rolf W. Hartmann، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2008
Pages :
19
From page :
1992
To page :
2010
Abstract :
Novel chemical entities were prepared via Suzuki and SN 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, t1/2 9.5 h vs 1.6 h). Docking studies revealed two new binding modes different from the one of the substrates and steroidal inhibitors.
Keywords :
Molecular electrostatic potential maps , Prostate cancer , Steroidomimetics , 17?-Hydroxylase-17 , Hepatic CYPs , Pharmacokinetic studies , Testosterone plasma concentrations , Docking studies , 20-lyase (CYP17) inhibitors
Journal title :
Bioorganic and Medicinal Chemistry
Serial Year :
2008
Link To Document :
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