154229-21-7

Basic information

• Product Name: 17-(3-pyridyl)androsta-5,16-dien-3-one
• Synonyms: 17-(3-pyridyl)androsta-5,16-dien-3-one;7-(3-pyridyl)androsta-5,16-dien-3-one;17-(3-pyridinyl)-androsta-4,16-diene-3-one;D4-abiraterone (CB-7627)
• CAS NO: 154229-21-7
• Molecular Formula: C₂₄H₂₉NO
• Molecular Weight: 347.49
• Mol File: 154229-21-7.mol

Chemical Properties

• Boiling Point: 504.6°Cat760mmHg
• Flash Point: 259.9°C
• Appearance: /
• Density: 1.14g/cm³
• Vapor Pressure: 2.63E-10mmHg at 25°C
• Refractive Index: 1.598
• Storage Temp.: 2-8°C
• PKA: 5.32±0.12(Predicted)
• CAS DataBase Reference: 17-(3-pyridyl)androsta-5,16-dien-3-one(CAS DataBase Reference)
• NIST Chemistry Reference: 17-(3-pyridyl)androsta-5,16-dien-3-one(154229-21-7)
• EPA Substance Registry System: 17-(3-pyridyl)androsta-5,16-dien-3-one(154229-21-7)

Safety Data

• Hazardous Substances Data: 154229-21-7(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
17-(3-Pyridyl)androsta-5,16-dien-3-one is used as a steroidal inhibitor for human cytochrome P450 17α-hydroxylase-C17,20-lyase. This enzyme plays a crucial role in the biosynthesis of steroid hormones, such as cortisol and sex hormones. By inhibiting this enzyme, the compound can potentially be used in the treatment of conditions related to hormonal imbalances or overproduction.
Additionally, due to its structural similarity to natural steroids, 17-(3-Pyridyl)androsta-5,16-dien-3-one may also be utilized in the development of new drugs targeting steroid hormone-related disorders or as a precursor in the synthesis of other steroidal compounds with therapeutic potential.
Used in Chemical Research:
In the field of chemical research, 17-(3-Pyridyl)androsta-5,16-dien-3-one can serve as a valuable starting material for the synthesis of novel steroidal derivatives. Its unique pyridine ring substitution allows for further functionalization and modification, leading to the development of new compounds with enhanced biological activities or improved pharmacological properties.
Furthermore, the compound can be employed in the study of enzyme inhibition mechanisms, particularly targeting cytochrome P450 enzymes, which are involved in various metabolic processes and are often associated with drug metabolism and detoxification. Understanding the interaction between 17-(3-Pyridyl)androsta-5,16-dien-3-one and these enzymes can provide insights into the design of more effective and selective inhibitors for therapeutic applications.

InChI:InChI=1/C24H29NO/c1-23-11-9-18(26)14-17(23)5-6-19-21-8-7-20(16-4-3-13-25-15-16)24(21,2)12-10-22(19)23/h3-4,7,13-15,19,21-22H,5-6,8-12H2,1-2H3/t19-,21-,22-,23-,24+/m0/s1

Upstream product

• 154229-38-6 3-<2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy>-17-(3-pyridyl)androsta-3,5,16-triene 
• 853-23-6 prasterone acetate 
• 115375-60-5 3β-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate 
• 103708-01-6 3-<2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy>androsta-3,4-diene-17-one 
• 154229-37-5 3-<2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenoxy>androsta-3,5,16-trien-17-yl trifluoromethanesulfonate 
• 53-43-0 dehydroepiandrosterone 
• 89878-14-8 3-Diethylboranylpyridine 
• 100772-35-8 17-iodoandrosta-4,16-dien-3-one 
• 32138-69-5 17-iodo-5,16-androstadien-3-ol 
• 63015-10-1 dehydroepiandrosterone-17-hydrazone 
• 626-55-1 3-Bromopyridine 
• 63-05-8 Androstenedione 
• 972-46-3 3-ethoxyandrosta-3,5-dien-17-one 
• 154229-18-2 abiraterone acetate 

Downstream Products

• 154229-31-9 17-(3-pyridyl)androsta-4,16-dien-3-one oxime 
• 1382474-64-7 C₂₄H₃₀N₂O 
• 1382470-43-0 (5aR,7aS)-5a,7a-dimethyl-8-(pyridin-3-yl)-4,5,5a,5b,6,7,7a,10,10a,10b,11,12-dodecahydrocyclopenta[5,6]naphtho[1,2-d]azepin-2(3H)-one 
• 1382470-45-2 (5aR,7aS)-3,5a,7a-trimethyl-8-(pyridin-3-yl)-4,5,5a,5b,6,7,7a,10,10a,10b,11,12-dodecahydrocyclopenta[5,6]naphtho[1,2-d]azepin-2(3H)-one 
• 1382471-47-7 (5aR,7aS)-3,5a,7a-trimethyl-8-(pyridin-3-yl)-2,3,4,5,5a,5b,6,7,7a,10,10a,10b,11,12-tetradecahydrocyclopenta[5,6]naphtho[1,2-d]azepine 
• 154229-28-4 3-acetoxy-17-(pyridin-3-yl)androsta-3,5,16-triene 
• 154229-18-2 abiraterone acetate 
• 154229-19-3 abiraterone 

Relevant articles and documents

Slow-, tight-binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen

Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( Ki? = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of 214.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even whenmost abiraterone has been eliminated systemically. Subsequent pharmacokineticpharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, inwhich equipotent reduction of downstreamplasma DHEAsulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for reevaluating the current dosing paradigmof abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.

Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2

Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects.

A acetate synthesis method

The invention relates to a synthesis method of abiraterone acetate. According to the synthesis method of the abiraterone acetate, a compound 1 is taken as a revelator, and the abiraterone acetate is prepared through steps such as esterification, Grignard reagent reaction, dehydration, acylation, reduction, acetylation and the like.

ALTERING STEROID METABOLISM FOR TREATMENT OF STEROID-DEPENDENT DISEASE

A method of treating steroid-dependent disease such as prostate cancer in a subject is described that includes administering a therapeutically effective amount a CYP17A inhibitor and an effective amount of a 5- -reductase inhibitor to the subject.

A-ring modified steroidal azoles retaining similar potent and slowly reversible CYP17A1 inhibition as abiraterone

Abiraterone acetate is a potent inhibitor of human cytochrome P450c17 (CYP17A1, 17α-hydroxylase/17,20-lyase) and is clinically used in combination with prednisone for the treatment of castration-resistant prostate cancer. Although many studies have documented the potency of abiraterone (Abi) in a variety of in vitro and in vivo systems for several species, the exact potency of Abi for human CYP17A1 enzyme has not yet been determined, and the structural requirements for high-potency steroidal azole inhibitors are not established. We synthesized 4 Abi analogs differing in the A-B ring substitution patterns: 3α-hydroxy-Δ4-Abi (13), 3-keto- Δ4-Abi (11), 3-keto-5α-Abi (6), and 3α-hydroxy- 5α-Abi (5). We measured the spectral binding constants (Ks) using purified and modified human CYP17A1 along with the determination constants (Ki) applying a native human CYP17A1 enzyme in yeast microsomes for these compounds as well as for ketoconazole. For Abi, 3-keto- Δ4-Abi, 3-keto-5α-Abi, and 3α-hydroxy-5α-Abi, the type 2 spectral changes gave the best fit for a quadratic equation, since in these experiments Ks values were 0.1-2.6 nM, much lower than that for ketoconazole and 3α-hydroxy-Δ4-Abi (Ks values were 140 and 1660 nM, respectively). Inhibition experiments showed mixed inhibition patterns with Ki values of 7-80 nM. Abi dissociation from the CYP17A1-Abi complex was incomplete and slow; the t1/2 for dissociation was 1.8 h, with 55% of complex remaining after 5 h. We conclude that Abi and the 3 related steroidal azoles (3-keto-Δ4-Abi, 3-keto-5α-Abi, and 3α-hydroxy-5α-Abi), which also mimic natural substrates, are extraordinarily potent inhibitors of human CYP17A1, whereas the 3α-hydroxy-Δ4-Abi is moderately potent and comparable to ketoconazole.

CYP11B, CYP17, AND/OR CYP21 INHIBITORS

Provided herein are inhibitors of CYP11B, CYP17, and/or CYP21 enzymes of Formula (Z), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), or (XVII). Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat androgen-dependent diseases, disorders and conditions. Formula (Z)

17-substituted steroids useful in cancer treatment

Compounds of the general formula (1) STR1 wherein X represents the residue of the A, B and C rings of a steroid, R represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R 14 represents a hydrogen atom and R 15 represents a hydrogen atom or an alkyl or alkoxy group of 1-4 carbon atoms, or a hydroxy or alkylcarbonyloxy group of 2 to 5 carbon atoms or R 14 and R 15 together represent a double bond, and R 16 represents a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, in the form of the free bases or phannaceutically acceptable acid addition salts, are useful for treatment of androgen-dependent disorders, especially prostatic cancer, and also oestrogen-dependent disorders such as breast cancer.

Novel Steroidal Inhibitors of Human Cytochrome P45017α (17α-Hydroxylase-C17,20-lyase): Potential Agents for the Treatment of Prostatic Cancer

Steroidal compounds having a 17-(3-pyridyl) substituent together with a 16,17-double bond have been synthesized, using a palladium-catalyzed cross-coupling reaction of a 17-enol triflate with diethyl(3-pyridyl)borane, which are potent inhibitors of human testicular 17α-hydroxylase-C17,20-lyase.The requirement for these structural features is stringent: compounds having 2-pyridyl (9), 4-pyridyl (10), or 2-pyridylmethyl (11) substituents instead of the 3-pyridyl substituent were either poor inhibitors or noninhibitory.Reduction of the 16,17-double bond to give 17β-pyridyl derivatives diminished potency with 3-pyridyl substitution (327; IC50 for lyase, 2.923 nM) but increased it with a 4-pyridyl substituent present (1028; IC50 1 μM53 nM).In contrast, a variety of substitution patterns in rings A-C of the steroid skeleton afforded inhibitors having potencies similar to those most closely related structurally to the natural substrates pregnenolone and progesterone, respectively 17-(3-pyridyl)androsta-5,16-dien-3β-ol (3, Kiapp 1 nM; IC50 for lyase, 2.9 nM) and 17-(3-pyridyl)androsta-4,16-dien-3-one (15; IC50 for lyase, 2.1 nM).Thus compounds having variously aromatic ring A (18), saturated rings A/B (21,22), and oxygenated ring C (26) exhibited IC50 values for lyase (1.8-3.0 nM) falling within a 2-fold range.The most potent compounds are candidates for development as drugs for the treatment of hormone-dependent prostatic carcinoma.