Ketodarolutamide (ORM-15341)

hAR (IC50 = hAR )

ODM-201及其药理活性主要代谢产物ORM-15341是新颖的，在结构上不同于任何已知的抗雄激素，包括第二代抗雄激素恩杂鲁胺和ARN-509。图1A、B显示了ODM-201和ORM-15341的化学结构。[1]
在竞争性AR结合试验中，ODM-201和ORM-15341的抑制常数（Ki）值分别为11和8 nM，明显低于在相同条件下测试的恩杂鲁胺（86 nM）和ARN-509（93 nM）（图1C）。ODM-201及其主要代谢产物ORM-15341也是人类AR（hAR）的强效完全拮抗剂，IC50值为26和38 nM，如稳定表达全长hAR和雄激素反应性萤光素酶报告基因构建体的AR-HEK293细胞中的转录激活试验所示。[1]
相比之下，在ODM-201、ORM-15341、恩杂鲁胺或ARN-509存在的情况下，AR主要是细胞质的，表明这些抗雄激素在相同程度上抑制了雄激素诱导的过表达AR的核转位[1]。

为了阐明ODM-201在CRPC小鼠模型中的体内疗效，皮下注射VCaP细胞的去势雄性裸鼠口服ODM-201（50mg/kg）一次（qd）或每日两次（bid），或用恩杂鲁胺（20mg/kg，qd）治疗37天。恩杂鲁胺的剂量是根据之前发表的体内研究9和我们的药代动力学（PK）分析选择的，这些研究表明，在小鼠中，该剂量恩杂鲁酰胺的全身暴露量（AUC0-24）是ODM-201（50mg/kg，bid）的2.5倍。此外，恩杂鲁胺显示出较长的血浆半衰期（18.3小时），而ODM-201在小鼠体内的半衰期不是最佳的（1.6小时），支持恩杂鲁肽每日一次给药和ODM-201的更高剂量和更频繁给药。恩杂鲁胺和ODM-201的PK数据见补充表S1[1]。

[1]. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms toandrogen signaling-directed prostate cancer therapies. Sci Rep. 2015 Jul 3;5:12007. doi: 10.1038/srep12007.

[2]. Preparation of heteroaryl carboxamides as androgen receptor modulators. From PCT Int. Appl. (2012), WO 2012143599 A1 20121026.

Ketodarolutamide, a nonsteroidal antiandrogen (NSAA), is the major active metabolite of [darolutamide].

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Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.[1]

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In summary, ODM-201 is a high-activity, next-generation AR inhibitor, which antagonizes AR mutants AR(F876L), AR(W741L), and AR(T877A) known to mediate resistance to first- and second-generation antiandrogens. ODM-201 also functions as an antagonist in AR overexpressing cells and impairs nuclear translocation of the receptor. In nonclinical in vitro and in vivo models of CRPC, ODM-201 is more efficacious than other tested antiandrogens and it does not stimulate androgen feedback loop at the hypothalamic-pituitary-gonadal axis. Taken together, these results indicate that ODM-201 exhibits unique properties that may offer advantages for the treatment of CRPC over the first- and second-generation antiandrogens. These nonclinical findings have been translated to significant antitumor activity and a good tolerability and safety profile observed in phase 1 and 2 clinical trials in men with metastatic CRPC28. In these trials, PSA response (50% or greater decrease) was present at 86% of chemotherapy-naïve patients at 700 mg twice daily dose.[1]

C₁₉H₁₇CLN₆O₂

396.83

396.11

C, 57.51; H, 4.32; Cl, 8.93; N, 21.18; O, 8.06

1297537-33-7

1297537-33-7;

52919826

White to off-white solid powder

3.21

116.46

2

5

6

28

637

1

ClC1=C(C#N)C=CC(=C1)C1C=CN(C[C@H](C)NC(C2=CC(C(C)=O)=NN2)=O)N=1

GMBPVBVTPBWIKC-NSHDSACASA-N

InChI=1S/C19H17ClN6O2/c1-11(22-19(28)18-8-17(12(2)27)23-24-18)10-26-6-5-16(25-26)13-3-4-14(9-21)15(20)7-13/h3-8,11H,10H2,1-2H3,(H,22,28)(H,23,24)/t11-/m0/s1

3-acetyl-N-[(2S)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-1H-pyrazole-5-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.30 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.5 mg/mL (6.30 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.30 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。