851983-85-2

Usage

Uses

Used in Pharmaceutical Industry:
Galeterone is used as an androgen receptor antagonist and CYP17A1 enzyme inhibitor for the treatment of prostate cancer. Its novel triple mechanism of action makes it a promising candidate for managing the disease, particularly in cases of castration-resistant prostate cancer (CRPC).
Used in Clinical Research:
Galeterone is used in trials studying the treatment of prostate cancer, where it has shown significant anti-tumor activity and a well-tolerated safety profile. This makes it a valuable asset in the ongoing search for effective therapies against prostate cancer, particularly for patients with CRPC who have limited treatment options.

Biological Activity

The cytochrome P450 (CYP) isoform CYP17 is also known as steroid 17α-hydroxylase/17,20 lyase because it catalyzes both 17α-hydroxylase and 17,20 lyase reactions in the synthesis of steroids, including androgens, estrogens, glucocorticoids, and mineralocorticoids. Galeterone is a CYP17 inhibitor (IC50 = 300 nM) that has been shown to competitively block synthetic androgen binding (EC50 = 845 nM) and to antagonize the androgen receptor in transcriptional activation assays. Galeterone can inhibit the growth of castration-resistant prostate cancer cells with an IC50 value of 2.9 μM and demonstrates synergy with everolimus or gefitinib for growth inhibition.

Mode of action

Galeterone is an orally bioavailable small-molecule androgen receptor modulator and CYP17 lyase inhibitor with potential antiandrogen activity. Galeterone exhibits three distinct mechanisms of action: 1) as an androgen receptor antagonist, 2) as a CYP17 lyase inhibitor and 3) by decreasing overall androgen receptor levels in prostate cancer tumors, all of which may result in a decrease in androgen-dependent growth signaling. Localized to the endoplasmic reticulum (ER), the cytochrome P450 enzyme CYP17 (P450C17 or CYP17A1) exhibits both 17alpha-hydroxylase and 17,20-lyase activities, and plays a key role in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.

references

[1]. devore n m, & scott e e. structures of cytochrome p450 17a1 with prostate cancer drugs abiraterone and tok-001. nature, 2012, 482: 116-119.[2]. mallik i, davila m, tapia t, et al. androgen regulates cdc6 transcription through interactions between androgen receptor and e2f transcription factor in prostate cancer cells. biochimica et biophysica acta (bba) - molecular cell research, 2008,1783:1737-1744.[3]. bruno r d, vasaitis t s, gediya l. k, et al. synthesis and biological evaluations of putative metabolically stable analogs of vn/124-1 (tok-001): head to head anti-tumor efficacy evaluation of vn/124-1 (tok-001) and abiraterone in lapc-4 human prostate cancer xenograft model. steroids, 2011,76: 1268-1279.

Upstream product

• 851895-78-8 3-β-acetoxy-17-(1H-benzimidazol-1-yl)-16-formyl-androsta-5,16-diene 
• 851895-79-9 3β-acetoxy-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene 
• 1865-56-1 3β-acetoxy-17-chloro-16-formylandrost-5,16-diene 
• 51-17-2 benzoimidazole 

Downstream Products

• 1189049-81-7 3β-O-sulfamoyl-17-(1H-benzimidazol-1-yl)androsta-5,16-dien 
• 1338684-01-7 3β-mesyloxy-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene 
• 1338684-03-9 3β-hydroxy-17-(1H-benzimidazol-1-yl)androsta-5-ene 
• 1338684-00-6 3ξ-fluoro-17-(1H-benzimidazol-1-yl)androsta-5,16-dien 
• 1338684-02-8 3α-azido-17-(1H-benzimidazol-1-yl)androsta-5,16-diene 
• 1441047-00-2 3β-tosyloxy-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene 
• 1441047-05-7 3β-(pyridine-2-carboxylate)-17-(1H-benzimidazol-1-yl)-androsta-5,16-diene 

Relevant academic research and scientific papers

PROCESS FOR THE PREPARATION OF GALETERONE

A process for the synthesis of 3β-hydroxy-17-(1H-benzimidazol-1-yl)androsta-5,16-diene is described, a compound also known as Galeterone and used in the treatment of prostate cancer, having the formula (I) given below.

NOVEL COMPOSITIONS AND METHODS FOR TREATING PROSTATE CANCER

Described herein are compounds, methods of making such compounds, pharmaceutical compositions, and medicaments comprising such compounds, and methods of using such compounds to treat androgen receptor mediated diseases or conditions. In some embodiments, the solid matrix comprises a polymer. In some embodiments, the polymer is soluble in an aqueous solution. In particular embodiments, the aqueous solution is water. In other embodiments, the aqueous solution has a pH of 5.0 or greater.

Discovery and development of galeterone (TOK-001 or VN/124-1) for the treatment of all stages of prostate cancer

In our effort to discover potent and specific inhibitors of 17α-hydroxylase/17,20-lyase (CYP17), the key enzyme which catalyzes the biosynthesis of androgens from progestins, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Galeterone or TOK-001, formerly called VN/124-1) was identified as a selective development candidate which modulates multiple targets in the androgen receptor (AR) signaling pathway. This drug annotation summarizes the mechanisms of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for galeterone, which has successfully completed phase II clinical development in men with castration resistant (advanced) prostate cancer (CRPC). Phase III clinical studies in CRPC patients are scheduled to begin in early 2015.

BIOMARKERS FOR TREATMENT OF NEOPLASTIC DISORDERS USING ANDROGEN-TARGETED THERAPIES

Described herein are methods and compositions for the treatment of prostate cancer in a subject in need thereof. The prostate cancer may be a castration resistant and an androgen receptor antagonist-resistant prostate cancer. The methods may comprise administering to the subject a CYP17-lyase inhibitor of Formula II.

ANDROGEN RECEPTOR DOWN-REGULATING AGENTS AND USES THEREOF

The present disclosure provides the design and synthesis of novel steroidal compounds that cause down-regulation of the androgen receptor (AR), both full length and splice variant. The compounds are potential agents for the treatment of all forms of prostate cancer and other diseases that depend on functional AR.

Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer

As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl) androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5, 16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5, 16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer.

NOVEL 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 (azabenzoazoles) 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 prodrug 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.

NOVEL C-17-HETEROARYL STEROIDAL CYP17 INHIBITORS/ANTIANDROGENS: SYNTHESIS, IN VITRO BIOLOGICAL ACTIVITIES, PHARMACOKINETICS AND ANTITUMOR ACTIVITY

Described are steroidal C-17 benzoazoles, pyrimidinoazoles (azabenzoazoles) and diazines. Methods for their synthesis are also described, which include methods having a step of nucleophilic vinylic "addition-elimination" substitution reaction of 3F-acetoxy-17-chloro-16-formylandrosta-5,16-diene or analogs thereof and benzoazole or pyrimidinoazole nucleophiles and methods having a palladium catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3F-ol or analogs thereof with tributylstannyl diazines. The compounds are potent inhibitors of human CYP 17 enzyme as well as potent antagonists of both wild type and mutant androgen receptors (AR). The compounds are useful for the treatment of human prostate cancer. "

Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: Synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model

New chemical entities, steroidal C-17 benzoazoles (5, 6, 9 and 10) and pyrazines (14 and 15) were rationally designed and synthesized. The key reaction for synthesis of the benzoazoles involved the nucleophilic vinylic "addition-elimination" substitution reaction of 3β-acetoxy-17- chloro-16-formylandrosta-5,16-diene (2) and benzoazole nucleophiles, while that for synthesis of pyrazines involved palladium-catalyzed cross-coupling reaction of 17-iodoandrosta-5,16-dien-3β-ol (13) with tributylstannyl diazines. Some of the compounds were shown to be potent inhibitors of human CYP17 enzyme as well as potent antagonist of both wild type and mutant androgen receptors (AR). The most potent CYP17 inhibitors were 3β-hydroxy-17-(1H-benzimidazole-1-yl) androsta-5,16-diene (5, code named VN/124-1), 3β-hydroxy-17-(5 1-pyrimidyl)androsta-5,16-diene (15) and 17-(1H-benzimidazole-1-yl) androsta-4,16-dien-3-one (6), with IC50 values of 300, 500 and 915 nM, respectively. Compounds 5, 6, 14 and 15 were effective at preventing binding of 3H-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant LNCaP AR and the wild-type AR, but with a 2.2- to 5-fold higher binding efficiency to the latter. Compounds 5 and 6 were also shown to be potent pure AR antagonists. The cell growth studies showed that 5 and 6 inhibit the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC 50 values in the low micromolar range (i.e., 10 μM). Their inhibitory potencies were comparable to that of casodex but remarkably superior to that of flutamide. The pharmacokinetics of compounds 5 and 6 in mice were investigated. Following s.c. administration of 50 mg/kg of 5 and 6, peak plasma levels of 16.82 and 5.15 ng/mL, respectively, occurred after 30 to 60 min, both compounds were cleared rapidly from plasma (terminal half-lives of 44.17 and 39.93 min, respectively), and neither was detectable at 8 h. Remarkably, compound 5 was rapidly converted into a metabolite tentatively identified as 17-(1H-benzimidazol-1-yl)androsta-3-one. When tested in vivo, 5 proved to be very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft, while 6 was ineffective. Compound 5 (50 mg/kg/twice daily) resulted in a 93.8% reduction (P = 0.00065) in the mean final tumor volume compared with controls, and it was also significantly more effective than castration. To our knowledge, this is the first example of an antihormonal agent (an inhibitor of androgen synthesis (CYP17 inhibitor)/antiandrogen) that is significantly more effective than castration in suppression of androgen-dependent prostate tumor growth. In view of these impressive anticancer properties, compound 5 is a strong candidate for development for the treatment of human prostate cancer.