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.
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.
Jagusch
Carsten
C
Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041 Saarbrücken, Germany.
Negri
Matthias
M
Hille
Ulrike E
UE
Hu
Qingzhong
Q
Bartels
Marc
M
Jahn-Hoffmann
Kerstin
K
Pinto-Bazurco Mendieta
Mariano A E
MA
Rodenwaldt
Barbara
B
Müller-Vieira
Ursula
U
Schmidt
Dirk
D
Lauterbach
Thomas
T
Recanatini
Maurizio
M
Cavalli
Andrea
A
Hartmann
Rolf W
RW
D001665:Binding Sites; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013739:Testosterone / Q000097:blood
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007093:Imidazoles; D011084:Polycyclic Aromatic Hydrocarbons; D013739:Testosterone; D013254:Steroid 17-alpha-Hydroxylase