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Daridorexant | CAS No: 1505484-82-1 | GMP-certified suppliers
A medication that treats adult insomnia by improving sleep onset and maintenance while minimizing next-day residual sedation and supporting daytime functioning.
Therapeutic categories
Central Nervous System DepressantsCytochrome P-450 CYP3A SubstratesCytochrome P-450 CYP3A4 SubstratesCytochrome P-450 SubstratesOrexin Receptor AntagonistsWakefulness-Promoting Agents
Generic name
Daridorexant
Molecule type
small molecule
CAS number
1505484-82-1
DrugBank ID
DB15031
Approval status
Approved drug
Primary indications
- In the US and Europe, daridorexant is indicated for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance
- [L39655, L46307] The European prescribing information states that insomnia should be characterized by symptoms that are present for at least three months and have a considerable impact on daytime functioning
Product Snapshot
- Daridorexant is available as an orally administered film-coated tablet formulation
- It is indicated for the treatment of insomnia in adult patients exhibiting difficulties with sleep onset and/or sleep maintenance
- Daridorexant holds regulatory approval in major markets including the US and European Union
Clinical Overview
Daridorexant (CAS Number 1505484-82-1) is a selective dual orexin receptor antagonist indicated for the treatment of insomnia in adult patients. Insomnia is characterized by difficulties with sleep onset and/or maintenance, accompanied by impaired daytime functioning. The European label specifies that symptoms should persist for at least three months and significantly impact daily activities.
Pharmacologically, daridorexant acts by selectively blocking orexin receptors OX1R and OX2R, which are G-protein coupled receptors involved in the regulation of wakefulness. Orexins, also known as hypocretins, are neuropeptides produced in the lateral hypothalamus that promote arousal by activating various wake-promoting neuronal pathways, including histaminergic, noradrenergic, serotonergic, dopaminergic, and cholinergic systems. Daridorexant exhibits equipotent antagonism at OX1R and OX2R with Ki values of 0.47 and 0.93 nM respectively, thereby suppressing the wake drive and facilitating the initiation and maintenance of sleep without the broad CNS depressant effects seen with GABA-A receptor modulators.
Clinical trials have demonstrated daridorexant’s efficacy in improving sleep onset, sleep maintenance, and total sleep time, while also reducing patient-reported daytime sleepiness. Safety data indicate minimal risk for next-morning residual sedation; no clinically significant QTc prolongation has been observed, even at doses four times the maximum recommended. Abuse potential studies reveal some risk at supratherapeutic doses, with drug liking comparable to zolpidem and suvorexant in recreational users, but no physical dependence or withdrawal symptoms upon discontinuation have been reported.
Daridorexant is metabolized primarily by cytochrome P450 CYP3A4 enzymes. It was approved by the FDA in January 2022 under the brand name QUVIVIQ and subsequently approved by the European Commission in May 2022 and Health Canada in April 2023. It is classified within central nervous system depressants, orexin receptor antagonists, and CYP3A substrates.
For API sourcing, ensuring compliance with regulatory standards for purity, impurity profiling, and consistency is critical due to the compound’s CNS activity and metabolic pathway. Verification of manufacturing under Good Manufacturing Practices (GMP) and robust analytical characterization to detect potential isomeric forms or degradation products is recommended.
Pharmacologically, daridorexant acts by selectively blocking orexin receptors OX1R and OX2R, which are G-protein coupled receptors involved in the regulation of wakefulness. Orexins, also known as hypocretins, are neuropeptides produced in the lateral hypothalamus that promote arousal by activating various wake-promoting neuronal pathways, including histaminergic, noradrenergic, serotonergic, dopaminergic, and cholinergic systems. Daridorexant exhibits equipotent antagonism at OX1R and OX2R with Ki values of 0.47 and 0.93 nM respectively, thereby suppressing the wake drive and facilitating the initiation and maintenance of sleep without the broad CNS depressant effects seen with GABA-A receptor modulators.
Clinical trials have demonstrated daridorexant’s efficacy in improving sleep onset, sleep maintenance, and total sleep time, while also reducing patient-reported daytime sleepiness. Safety data indicate minimal risk for next-morning residual sedation; no clinically significant QTc prolongation has been observed, even at doses four times the maximum recommended. Abuse potential studies reveal some risk at supratherapeutic doses, with drug liking comparable to zolpidem and suvorexant in recreational users, but no physical dependence or withdrawal symptoms upon discontinuation have been reported.
Daridorexant is metabolized primarily by cytochrome P450 CYP3A4 enzymes. It was approved by the FDA in January 2022 under the brand name QUVIVIQ and subsequently approved by the European Commission in May 2022 and Health Canada in April 2023. It is classified within central nervous system depressants, orexin receptor antagonists, and CYP3A substrates.
For API sourcing, ensuring compliance with regulatory standards for purity, impurity profiling, and consistency is critical due to the compound’s CNS activity and metabolic pathway. Verification of manufacturing under Good Manufacturing Practices (GMP) and robust analytical characterization to detect potential isomeric forms or degradation products is recommended.
Identification & chemistry
| Generic name | Daridorexant |
|---|---|
| Molecule type | Small molecule |
| CAS | 1505484-82-1 |
| UNII | LMQ24G57E9 |
| DrugBank ID | DB15031 |
Pharmacology
| Summary | Daridorexant is a dual antagonist of orexin receptors OX1R and OX2R, which are involved in regulating wakefulness through activation of multiple arousal-promoting neuronal pathways. By inhibiting orexin binding, daridorexant suppresses wake drive and facilitates the initiation and maintenance of sleep without affecting GABAergic neurotransmission. Its pharmacodynamic profile targets the orexinergic system to modulate the sleep-wake cycle in patients with insomnia characterized by difficulties in sleep onset and maintenance. |
|---|---|
| Mechanism of action | The sleep and wake cycle is regulated by complex interactions between sleep-promoting systems, including inhibitory GABA activity, and wake-promoting systems, including orexins, acetylcholine and monoaminergic systems. Orexin, also called hypocretin, is a wake-promoting neuropeptide produced by a small group of neurons in the lateral hypothalamus. Orexin stabilizes wakefulness by activating orexin neurons with the highest activity during active wakefulness and minimal activity during sleep. Orexin neurons project to other wake-promoting neurons that also express orexin receptors: these include the histaminergic neurons of the tuberomammillary nucleus, noradrenergic neurons of the locus coeruleus, serotoninergic neurons of the dorsal raphe, dopaminergic neurons of the ventral tegmental area, and cholinergic neurons of the basal forebrain and the pedunculopontine and laterodorsal tegmental nuclei. These wake-promoting neurons are part of the ascending reticular activating system that operates under a feedback loop in the sleep and wake cycle. There are two identified types of orexin (OXA and OXB) that bind to orexin type 1 and 2 receptors (OX1R and OX2R), which are G-protein coupled receptors. OXA binds more preferentially to OX1R, while OX2R shows a dual affinity for OXA and OXB. The defined role of each orexin receptor is still unclear; however, there is some evidence suggesting that OX2R regulates sleep and wake, while OX1R have some role in sleep maintenance. Daridorexant blocks the binding of wake-promoting neuropeptides OXA and OXB to OX1R and OX2R, thereby suppressing wake drive. Daridorexant selectively targets orexin neurons and inhibits downstream neuronal pathways that promote wakefulness; however, it does not affect neuronal pathways that cause side effects commonly seen in positive allosteric GABA-A receptor modulators. |
| Pharmacodynamics | Daridorexant binds to and antagonizes the orexin receptors OX1R and OX2R (Ki = 0.47 and 0.93 nM, respectively) equipotentally. In clinical trials, daridorexant improved sleep onset and sleep maintenance, and patient-reported total sleep time. Patient-reported daytime sleepiness was also reportedly reduced. At a dose four times the maximum recommended dose, daridorexant does not prolong the QTc interval to any clinically relevant extent. Daridorexant is currently being assessed for a controlled substance schedule in the US. In a human abuse potential study, daridorexant showed some abuse potential at doses higher than the recommended dose (100-150 mg), indicated by similar “drug liking” ratings to zolpidem (30 mg) and suvorexant in recreational sedative drug users. However, at clinically relevant concentrations, daridorexant does not bind to abuse-associated CNS targets. In animal studies and clinical trials evaluating physical dependence, chronic administration of daridorexant did not produce withdrawal signs or symptoms upon drug discontinuation, indicating that the drug does not produce physical dependence. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Orexin receptor type 1 | Humans | antagonist |
| Orexin receptor type 2 | Humans | antagonist |
ADME / PK
| Absorption | Daridorexant reaches peak plasma concentrations within one to two hours. Daridorexant has an absolute bioavailability of 62%. While a high-fat and high-calorie meal delayed the Tmax by 1.3 hours and decreased the Cmax by 16% in healthy subjects, the total exposure (AUC) was not affected. |
|---|---|
| Half-life | The terminal half-life is approximately 8 hours. |
| Protein binding | Daridorexant is 99.7% bound to plasma proteins. |
| Metabolism | Daridorexant undergoes extensive metabolism primarily mediated by CYP3A4 (89%), mostly via oxidative transformations. Other CYP enzymes individually contribute to less than 3% of metabolic clearance of daridorexant. |
| Route of elimination | The primary route of excretion is via feces, accounting for approximately 57% of drug excretion. About 28% of the drug is excreted via urine primarily in the form of metabolites. Trace amounts of the parent drug were found in feces and urine. |
| Volume of distribution | Daridorexant has a volume of distribution of 31 L. The blood to plasma ratio is 0.64. It effectively passes the blood-brain barrier. |
| Clearance | There is limited information on clearance. |
Formulation & handling
- Daridorexant is a small molecule API formulated for oral administration as film-coated tablets.
- It exhibits low water solubility and moderate lipophilicity (LogP 3.04), requiring formulation strategies to enhance bioavailability.
- Handle with consideration for CNS depressant effects; avoid co-administration with alcohol due to additive impairment risks.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient is under patent protection in the United States until at least mid-2033, with additional patents extending through late 2034. It is currently marketed in both the EU and US, indicating a mature presence in these regions. |
|---|
| Markets | EU, US |
|---|
Supply Chain
| Supply chain summary | Daridorexant is marketed under a single branded product name across both the US and EU markets, indicating a focused originator presence. Multiple patents protecting Daridorexant in the United States extend through mid-2033 to late 2034, suggesting that generic competition has not yet emerged and may be anticipated following these expiry dates. The current supply landscape is characterized by branded exclusivity with potential future opportunities for generic sourcing after patent expiration. |
|---|
Safety
| Toxicity | There is limited clinical experience with daridorexant overdose. In clinical pharmacology studies, healthy subjects were administered single doses of up to 200 mg, four times the maximum recommended dose. Somnolence, muscle weakness, cataplexy-like symptoms, sleep paralysis, disturbance in attention, fatigue, headache, and constipation were observed in these patients. There is no specific antidote to overdosage of daridorexant. In the event of an overdose, general symptomatic and supportive medical care, along with immediate gastric lavage where appropriate, should be provided in addition to careful monitoring. Dialysis is unlikely to be effective as daridorexant is highly protein-bound. |
|---|
High Level Warnings:
- Daridorexant exhibits central nervous system depressant effects
- Overdose symptoms may include somnolence, muscle weakness, cataplexy-like episodes, and cognitive disturbances
- No specific antidote is available
Daridorexant is a type of Central Nervous System Agents
Central Nervous System (CNS) Agents are a crucial category of pharmaceutical Active Pharmaceutical Ingredients (APIs) that specifically target the central nervous system. The CNS encompasses the brain and spinal cord, playing a vital role in regulating and controlling various bodily functions, including cognition, movement, emotions, and sensory perception. These agents are designed to interact with specific receptors, enzymes, or ion channels within the CNS to modulate neural activity and restore normal functioning.
CNS agents comprise a diverse range of pharmaceutical APIs, including analgesics, anesthetics, antipsychotics, sedatives, hypnotics, anti-epileptics, and antidepressants. Each subcategory addresses distinct neurological disorders and conditions. For instance, analgesics alleviate pain by targeting receptors in the brain and spinal cord, while antipsychotics are employed to manage psychosis symptoms in mental illnesses such as schizophrenia.
The development of CNS agents involves rigorous research, molecular modeling, and extensive clinical trials to ensure safety, efficacy, and specific target engagement. Pharmaceutical companies invest significant resources in identifying novel drug targets, synthesizing new compounds, and optimizing their pharmacological properties. These agents undergo rigorous regulatory evaluations and must adhere to stringent quality standards and guidelines.
Given the prevalence of CNS disorders globally, the market demand for effective CNS agents is substantial. The development of innovative CNS APIs not only improves patient outcomes but also provides valuable commercial opportunities for pharmaceutical companies. Continued advancements in CNS agent research and development hold the promise of groundbreaking therapies that can improve the quality of life for individuals affected by neurological conditions.
