hAR (IC50 = hAR )

ODM-201 and its pharmacologically active main metabolite ORM-15341 are novel and structurally distinct from any known antiandrogens including the second-generation antiandrogens enzalutamide and ARN-509. Figure 1A,B show the chemical structures of ODM-201 and ORM-15341. [1]
In competitive AR binding assays, the inhibition constant (Ki) values of ODM-201 and ORM-15341 were 11 and 8 nM, respectively, being clearly lower than those of enzalutamide (86 nM) and ARN-509 (93 nM) (Fig. 1C) that were tested under the same conditions. ODM-201 and its major metabolite ORM-15341 are also potent and full antagonists for human AR (hAR) with IC50 values of 26 and 38 nM as shown by transactivation assays in AR-HEK293 cells stably expressing full-length hAR and an androgen-responsive luciferase reporter gene construct. [1]
In contrast, in the presence of ODM-201, ORM-15341, enzalutamide, or ARN-509, AR was predominantly cytoplasmic, showing that these antiandrogens inhibit the androgen-induced nuclear translocation of overexpressed AR to same extent[1].

To elucidate the in vivo efficacy of ODM-201 in a CRPC mouse model, castrated male nude mice with subcutaneously injected VCaP cells were treated orally with ODM-201 (50 mg/kg) once (qd) or twice daily (bid), or with enzalutamide (20 mg/kg, qd) for 37 days. The dose for enzalutamide was selected based on previously published in vivo studies9 and our pharmacokinetic (PK) analyses which revealed that in mice the systemic exposure (AUC0–24) for this dose of enzalutamide was 2.5 times higher than that for ODM-201 (50 mg/kg, bid). Moreover, enzalutamide exhibited a long plasma half-life (18.3 hours) while the half-life of ODM-201 in mice was not optimal (1.6 hours) supporting once daily dosing for enzalutamide and higher dose and more frequent dosing for ODM-201. PK data for enzalutamide and ODM-201 are presented in Supplementary Table 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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.30 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.

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Solubility in Formulation 2: 2.5 mg/mL (6.30 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.30 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.

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 (Please use freshly prepared in vivo formulations for optimal results.)