RESUMEN
Dual CYP17/CYP11B2 inhibitors are proposed as a novel strategy for the treatment of prostate cancer to reduce risks of cardiovascular diseases. Via a combination of ligand- and structure-based approaches, a series of dual inhibitors were designed leading to the 2-(3-pyridyl)naphthalenes 10 and 11 with strong inhibition of both enzymes (IC50 values around 20 nM) and excellent selectivities over CYP11B1, CYP19, and CYP3A4. These compounds are considered as promising candidates for further in vivo evaluation.
Asunto(s)
Antineoplásicos/síntesis química , Enfermedades Cardiovasculares/inducido químicamente , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Naftalenos/síntesis química , Neoplasias de la Próstata/tratamiento farmacológico , Piridinas/síntesis química , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Humanos , Masculino , Modelos Moleculares , Naftalenos/química , Naftalenos/farmacología , Piridinas/química , Piridinas/farmacología , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidoresRESUMEN
Abiraterone, a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor (CYP17), is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen-dependent prostate cancer. Since steroidal compounds often show side effects attributable to their structure, we have tried to replace the sterane scaffold by nonsteroidal core structures. The design and synthesis of 20 new abiraterone mimetics are described. Their activities have been tested with recombinant human CYP17 expressed in E. coli. Promising compounds were further evaluated for selectivity against CYP11B1, CYP11B2, and the hepatic CYP3A4. Compounds 19 and 20 showed comparable activity to abiraterone (IC50 values of 144 and 64 nM vs 72 nM) and similar or even better selectivity against the other CYP enzymes. Selected compounds were also docked into our homology model, and the same binding modes as for abiraterone were found.
Asunto(s)
Androstenoles/síntesis química , Androstenoles/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Androstenos , Androstenoles/uso terapéutico , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Humanos , Masculino , Modelos Moleculares , Proteínas Recombinantes/efectos de los fármacosRESUMEN
Twenty-one novel compounds originating from two classes of annulated biphenyls were synthesized as mimetics of the steroidal A- and C-rings and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of the hepatic CYP enzyme 3A4. Potent CYP17 inhibitors were found for each class, compound 9 (17 and 71% at 0.2 and 2 microM, respectively) and 21 (591 nM). Compound 21 showed only weak inhibition of CYP3A4 (32 and 64% at 2 and 10 microM, respectively). Both compounds, however, exhibited moderate to strong inhibition of the glucocorticoid-forming enzyme CYP11B1. The most interesting compounds were docked into our protein model. They bound into one of the modes which we have previously published. New interaction regions were identified.
Asunto(s)
Compuestos de Bifenilo/química , Diseño de Fármacos , Inhibidores Enzimáticos , Imidazoles/química , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/enzimología , Humanos , Masculino , Modelos Moleculares , Conformación Molecular , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/enzimología , Esteroide 11-beta-Hidroxilasa/antagonistas & inhibidores , Esteroide 17-alfa-Hidroxilasa/biosíntesis , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Compuestos Heterocíclicos/farmacocinética , Imidazoles/farmacocinética , Modelos Moleculares , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Sitios de Unión , Disponibilidad Biológica , Inhibidores Enzimáticos/síntesis química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Concentración 50 Inhibidora , Hígado/enzimología , Hidrocarburos Policíclicos Aromáticos/química , Testosterona/sangreRESUMEN
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 microM, respectively), and little inhibition of the most important hepatic enzyme CYP3A4 (6% and 19% inhibition at 0.2 and 2 microM, respectively) and the key enzyme of glucocorticoid biosynthesis CYP11B1 (3% and 23% inhibition at 0.2 and 2 microM, respectively). Docking studies revealed that this compound does not assume the same binding mode as steroidal ligands.