Synthesis, biological evaluation and molecular modelling studies of novel ACD- and ABD-ring steroidomimetics as inhibitors of CYP17

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 1; pp. 267 - 273
• Main Authors: Pinto-Bazurco Mendieta, Mariano A.E., Negri, Matthias, Jagusch, Carsten, Hille, Ulrike E., Müller-Vieira, Ursula, Schmidt, Dirk, Hansen, Klaus, Hartmann, Rolf W.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 2008; Elsevier
• Subjects: 17α-hydroxylase-17,20-lyase (CYP17) inhibitors; Biological and medical sciences; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Docking studies; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hepatic CYPs; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; Liver - enzymology; Medical sciences; Models, Molecular; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; Pharmacology. Drug treatments; Progesterone - chemistry; Prostate cancer; Steroid 17-alpha-Hydroxylase - antagonists & inhibitors; Steroid 17-alpha-Hydroxylase - chemistry; Steroid 17-alpha-Hydroxylase - metabolism; Steroidomimetics; Urinary system; 17α-hydroxylase-17,20-lyase (CYP17) inhibitors; Hepatic CYPs; Docking studies; Steroidomimetics; Prostate cancer; Prostate disease; Isozyme; Steroid 17α-monooxygenase; Modeling; Pyridine derivatives; Structure activity relation; Molecular model; Chemical synthesis; Male genital diseases; Unspecific monooxygenase; Urinary system disease; Enzyme; Cytochrome P450; Malignant tumor; Naphthalene derivatives; In vitro; Phenols; Drug-metabolizing enzyme; Inhibitor; Oxidoreductases; Cancer
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.10.079

Novel ACD- and ABD-ring mimetics of progesterone were synthesised and evaluated as CYP17 inhibitors. One promising lead structure ( 15) was found, suitable for further optimisation. Two novel classes of non-steroidal substrate mimetics were synthesised and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of hepatic CYP enzymes 3A4, 1A2, 2C9 and 2C19. The most promising compound 15 showed a good inhibition of the target enzyme (31% and 66% at 0.2 and 2 μM, respectively), and little inhibition of the most important hepatic enzyme CYP3A4 (6% and 19% inhibition at 0.2 and 2 μM, respectively) and the key enzyme of glucocorticoid biosynthesis CYP11B1 (3% and 23% inhibition at 0.2 and 2 μM, respectively). Docking studies revealed that this compound does not assume the same binding mode as steroidal ligands.