Prodrugs of C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activities, pharmacokinetics and antitumor activity
Prodrugs of steroidal C-17 benzoazoles, pyrimidinoazoles (az-abenzoazoles) and diazines. Methods of synthesis are also described, whereby a prodrug group is substituted for a functional group at A ring portion of the ABC ring structure of the steroid. Suitable pro-drug groups include amino acid groups, succinate groups, phosphate groups, or sulfamate groups. The prodrugs of the disclosed compounds allow for improved oral bioavailability of the compounds that are inhibitors of human CYP 17 enzyme as well as potent antagonists of both wild type and mutant androgen receptors (AR). The compounds and the corresponding prodrugs are useful for the treatment of conditions such as human prostate cancer, breast cancer, and prostate hyperplasia.
1. A method of inducing apoptosis in a prostate cancer cell in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound of formula:
or a pharmaceutically-acceptable salt thereof, wherein the therapeutically-effective amount of the compound or the pharmaceutically-acceptable salt thereof is shown to induce apoptosis.
2. The method of claim 1 , wherein the apoptosis is associated with upregulation of an apoptosis-related protein.
3. The method of claim 2 , wherein the apoptosis-related protein is CCAAT/enhancer binding protein homologous transcription factor.
4. The method of claim 1 , wherein the prostate cancer is androgen-independent prostate cancer.
5. The method of claim 1 , wherein the induction of apoptosis is associated with an increase in intracellular calcium level in the cell.
6. The method of claim 1 , wherein the compound is formulated as a pharmaceutical composition.
7. The method of claim 6 , wherein the pharmaceutical composition is formulated for oral administration.
8. The method of claim 1 , wherein the therapeutically-effective amount is from about 1 mg to about 500 mg per day.
9. The method of claim 1 , wherein the subject is human.
10. The method of claim 1 , wherein the compound is a hydrochloride salt.
11. The method of claim 1 , wherein the apoptosis is associated with endoplasmic reticulum stress response.
12. The method of claim 1 , wherein the administering is performed ex vivo.