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N-desmethyl Enzalutamide (N-desmethyl MDV 3100) is an active metabolite of Enzalutamide which is is a novel, potent, orally bioavailable, organic, non-steroidal small molecule, second-generation androgen-receptor (AR) antagonist. Enzalutamide is an androgen-receptor (AR) antagonist with IC50 of 36 nM in LNCaP cells.
Physicochemical Properties
| Molecular Formula | C₂₀H₁₄F₄N₄O₂S |
| Molecular Weight | 450.41 |
| Exact Mass | 450.077 |
| Elemental Analysis | C, 53.33; H, 3.13; F, 16.87; N, 12.44; O, 7.10; S, 7.12 |
| CAS # | 1242137-16-1 |
| Related CAS # | Enzalutamide;915087-33-1;N-desmethyl Enzalutamide-d6;Enzalutamide carboxylic acid;1242137-15-0 |
| PubChem CID | 70678916 |
| Appearance | White to off-white solid powder |
| LogP | 4.562 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 31 |
| Complexity | 824 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | JSFOGZGIBIQRPU-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C20H14F4N4O2S/c1-19(2)17(30)27(11-4-3-10(9-25)14(7-11)20(22,23)24)18(31)28(19)12-5-6-13(16(26)29)15(21)8-12/h3-8H,1-2H3,(H2,26,29) |
| Chemical Name | 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-fluorobenzamide |
| Synonyms | N-desmethyl MDV 3100; N-desmethyl MDV-3100; N-desmethyl enzalutamide; 1242137-16-1; N-desmethylenzalutamide; 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamide; CHEMBL5171907; N-desmethyl MDV3100 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | AR/Androgen-receptor |
| ln Vitro | N-desmethylenzalutamide is a benzamide obtained by formal condensation of the carboxy group of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl}-2-fluorobenzoic acid with ammonia. It has a role as an antineoplastic agent and an androgen antagonist. It is a member of benzamides, an imidazolidinone, a nitrile, a thiocarbonyl compound, a member of (trifluoromethyl)benzenes and a member of monofluorobenzenes. |
| ln Vivo |
Because it is more effective than enzalutamide and shows similar primary efficacy and secondary pharmacodynamics, N-Desmethylenzalutamide is an active adjuvant that may have a role in the clinical effects of enzalutamide. Enzalutamide's glucosamine metabolite is pharmacologically inert and has a circulating concentration that is roughly 25% less than enzalutamide's [1]. Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4. Conclusions: If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.[1] |
| Enzyme Assay | Study with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 Substrates The pharmacokinetic parameters for enzalutamide and its major metabolites (Table 4) confirmed that plasma exposures in this study were similar to those observed in other studies in which enzalutamide was administered at 160 mg once daily to steady state [4]. The mean Ctrough values for enzalutamide, N-desmethyl enzalutamide, the carboxylic acid metabolite, and the sum of enzalutamide plus N-desmethyl enzalutamide were 12.0, 10.6, 6.32, and 23.0 μg/mL, respectively.[1] |
| Animal Protocol | A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg).[1] |
| ADME/Pharmacokinetics |
Study with Strong CYP2C8 and CYP3A4 Inhibitors As evidenced in Fig. 2, gemfibrozil decreased the rates of elimination of enzalutamide and formation of N-desmethyl enzalutamide while increasing the rate of formation of the carboxylic acid metabolite; these rates changed suddenly when gemfibrozil was discontinued on day 22. Given the apparent changes in pharmacokinetics of N-desmethyl enzalutamide after discontinuation of gemfibrozil, extrapolation of the observed concentration–time data in the terminal phase could not be used to estimate the magnitude of the effect of gemfibrozil on AUC∞. To address this issue, pharmacokinetic models were used to simulate concentration–time profiles for enzalutamide and metabolites for enzalutamide administered alone and enzalutamide coadministered with continuous gemfibrozil (i.e., no discontinuation on day 22) (Electronic Supplementary Material 1). Simulated concentration–time data for each of the 41 subjects in the study were then analyzed by NCA methods to estimate AUC∞ values. As AUC18 d and Cmax were defined by plasma concentration–time data prior to gemfibrozil discontinuation on day 22, these parameters were estimated by NCA analysis of observed data. [1] As indicated by the geometric mean ratios (GMRs; Table 3), gemfibrozil had the following effects on enzalutamide and the active metabolite: for enzalutamide, AUC18 d and AUC∞ increased by 2.53-fold and 4.26-fold, respectively, while Cmax decreased by 18 %; for N-desmethyl enzalutamide, AUC18 d, AUC∞, and Cmax decreased by 67, 25, and 44 %, respectively; and for the composite sum of enzalutamide plus N-desmethyl enzalutamide, AUC18 d and AUC∞ increased by 1.39-fold and 2.17-fold, respectively, while Cmax decreased by 16 %. Notably, the estimated magnitude of the effect of gemfibrozil on the sum of exposure to active moieties (enzalutamide plus N-desmethyl enzalutamide) was smaller for the AUC term based on observed data (AUC18 d) than for the AUC term based on modeling and simulation (AUC∞).[1] Itraconazole appeared to have only a small impact on the elimination of enzalutamide and the rates of formation of N-desmethyl enzalutamide and the carboxylic acid metabolite (Fig. 2); therefore, all pharmacokinetic parameters for assessing the itraconazole drug interaction were based on observed data. As indicated by the GMR values (Table 3), itraconazole had the following effects on enzalutamide and the active metabolite: for enzalutamide, AUC18 d and AUC∞ increased 1.34-fold and 1.41-fold, respectively, while Cmax decreased by 2 %; for N-desmethyl enzalutamide, AUC18 d decreased by 4 %, AUC∞ increased 1.21-fold, and Cmax decreased by 14 %; and for the sum of enzalutamide plus N-desmethyl enzalutamide, AUC18 d and AUC∞ increased 1.14-fold and 1.28-fold, respectively, while Cmax decreased by 3 %.[1] |
| Toxicity/Toxicokinetics | No deaths, serious adverse events, or adverse events resulting in discontinuation occurred during the healthy subject study with CYP2C8 and CYP3A4 inhibitors. Thirteen subjects (three in arm 1, six in arm 2, and four in arm 3) experienced at least one treatment-emergent adverse event (TEAE). All events were categorized as National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 1, with the exception of grade 2 flatulence in one subject (arm 2) that was attributed to a possible relationship to gemfibrozil. Four additional subjects experienced at least one TEAE that was attributed a possible relationship to the study drug. All TEAEs resolved by the end of the study. In the patient study with CYP substrates, the most frequent TEAEs (i.e., in at least three of 14 patients, ≥21.4 %) were nausea, constipation, dizziness, arthropod bite, fatigue, and hot flush. The majority of reported TEAEs were NCI-CTCAE grade 1 or 2. One patient experienced a single and transient episode of generalized tonic–clonic seizure that was assessed as probably related to enzalutamide and led to discontinuation of study treatment with enzalutamide. No clinically significant changes were noted for safety laboratory tests or electrocardiograms.[1] |
| References |
[1]. Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet. 2015 Oct;54(10):1057-69. |
| Additional Infomation | N-desmethylenzalutamide is a benzamide obtained by formal condensation of the carboxy group of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl}-2-fluorobenzoic acid with ammonia. It has a role as an antineoplastic agent and an androgen antagonist. It is a member of benzamides, an imidazolidinone, a nitrile, a thiocarbonyl compound, a member of (trifluoromethyl)benzenes and a member of monofluorobenzenes. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~222.02 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2202 mL | 11.1010 mL | 22.2020 mL | |
| 5 mM | 0.4440 mL | 2.2202 mL | 4.4404 mL | |
| 10 mM | 0.2220 mL | 1.1101 mL | 2.2202 mL |