Darolutamide
[CAS# 1297538-32-9]

Identification

• Classification: API >> Hormone and endocrine-regulating drugs
• Name: Darolutamide
• Synonyms: N-[(2S)-1-[3-(3-chloro-4-cyanophenyl)pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide
• Molecular Formula: C₁₉H₁₉ClN₆O₂
• Molecular Weight: 398.85
• CAS Registry Number: 1297538-32-9
• EC Number: 829-313-8
• SMILES: C[C@@H](CN1C=CC(=N1)C2=CC(=C(C=C2)C#N)Cl)NC(=O)C3=NNC(=C3)C(C)O

Properties

• Solubility: Insoluble (4.0E^-3 g/L) (25 ºC), Calc.^*, 44 mg/mL (DMSO) (Expl.)
• Density: 1.41±0.1 g/cm³ (20 ºC 760 Torr), Calc.^*
• Index of Refraction: 1.681, Calc.^*
• Boiling Point: 719.5±60.0 ºC (760 mmHg), Calc.^*
• Flash Point: 388.9±32.9 ºC, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P280-P305+P351+P338

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Acute hazardous to the aquatic environment	Aquatic Acute	1	H400
Acute toxicity	Acute Tox.	4	H302

Discovory and Applicatios

Darolutamide is a nonsteroidal androgen receptor inhibitor developed to treat non-metastatic castration-resistant prostate cancer (nmCRPC). The development of darolutamide stemmed from a need for effective therapies with fewer side effects compared to earlier androgen receptor inhibitors. It was discovered through extensive structure-activity relationship studies aimed at optimizing the binding affinity to the androgen receptor while reducing central nervous system penetration. This selective targeting minimizes neurological side effects often associated with similar agents, such as fatigue and seizures.

The molecular structure of darolutamide consists of a dihydropyrimidine core and a fluorophenyl group, contributing to its high affinity and specificity for the androgen receptor. Unlike other androgen receptor inhibitors like enzalutamide or apalutamide, darolutamide exhibits a unique binding mode, preventing the receptor from translocating into the nucleus and thus inhibiting the transcription of genes that drive cancer cell proliferation. Its lower blood-brain barrier penetration also sets it apart, resulting in a reduced likelihood of neurotoxicity.

Darolutamide was approved by the U.S. Food and Drug Administration (FDA) in 2019 following the pivotal ARAMIS trial. In this Phase III study, darolutamide demonstrated a significant improvement in metastasis-free survival compared to a placebo in patients with nmCRPC. The drug was well-tolerated, with a side effect profile comparable to the placebo group, which highlighted its safety advantage. This trial established darolutamide as a critical option for delaying disease progression in patients resistant to standard androgen deprivation therapy.

In clinical practice, darolutamide is administered orally, typically in combination with ongoing androgen deprivation therapy. It provides an effective treatment for nmCRPC patients who are at high risk of developing metastatic disease. The efficacy and tolerability of darolutamide have positioned it as a preferred choice for patients who may not tolerate other androgen receptor inhibitors due to their neurological side effects.

Ongoing research aims to expand the use of darolutamide into other stages of prostate cancer, including metastatic hormone-sensitive prostate cancer (mHSPC). Investigations into combination therapies with other agents, such as chemotherapy or novel hormonal treatments, are also underway to enhance therapeutic outcomes. The development of darolutamide reflects a significant advancement in targeted prostate cancer therapy, offering improved quality of life and survival benefits for patients.

References

2024. Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 42(36).
DOI: 10.1200/jco-24-01798

2024. Comprehensive review of cardiovascular disease in prostate cancer: epidemiology, risk factors, therapeutics and prevention strategies. Prostate Cancer and Prostatic Diseases, 27(4).
DOI: 10.1038/s41391-024-00897-x

2015. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Scientific Reports, 5(12007).
DOI: 10.1038/srep12007