The Quest for the Best Dual Orexin Receptor Antagonist (Daridorexant) for the Treatment of Insomnia Disorders

Boss, Christoph; Gatfield, John; Brotschi, Christine; Heidmann, Bibia; Sifferlen, Thierry; Raumer, Markus von; Schmidt, Günther; Williams, Jodi T.; Treiber, Alexander; Roch, Catherine

doi:10.1002/cmdc.202000453

Cited by 31 publications

(39 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ANOVA, analysis of variance. Full experimental details provided by Boss et al 2020 Daridorexant reduced the latency to persistent non-REM sleep and REM sleep both following administration at the beginning of the inactive (Fig. 3e) and the active phase (Fig.…”

Section: Promotion Of Sleep By Daridorexant Depends On Time Of the Day Sleep Pressure And Orexin Levelsmentioning

confidence: 99%

“…Data were integrated over 5-min time intervals and presented as mean ± standard error of the mean of 6-10 dogs per group. Data-on-file; full experimental details provided by Boss et al 2020 greater than the dose that increased sleep (Uslaner et al 2013). In contrast, monkeys treated with positive GABA-A receptor modulators showed impaired performance in both tasks.…”

Section: Preservation Of Cognition and Memorymentioning

confidence: 99%

“…Daridorexant (ACT-541468) is a new DORA that successfully completed two phase 3 clinical trials in insomnia in 2020. This compound was discovered through an intensive drug discovery program on orexin receptor antagonists (Boss et al 2020 ) that ensued following the discovery of almorexant (Brisbare-Roch et al 2007 ). The goal was to identify a potent, dual, and brain-penetrant orexin receptor antagonist with fast onset and a duration of action, long enough for covering the night, but short enough to avoid residual activity the following morning, at optimal efficacious doses.…”

Section: Introductionmentioning

confidence: 99%

“…Data-on-file. Full experimental details provided byBoss et al 2020 Efficacy of day-or nighttime administration of daridorexant on sleep promotion in rats. Rats are nocturnal animals as illustrated by the wakefulness (a) and sleep (b) profile over 24 h, depicted in 1 h bins; wakefulness is higher during the 12-h dark phase (gray rectangle).…”

mentioning

confidence: 99%

“…Data-on-file. Further experimental details provided byBoss et al 2020 (EEG) recordings. Cataplexy is a sudden episode of muscle weakness triggered by emotions, without impairment of consciousness, typically observed in narcolepsy type 1 that is caused by orexin neuron loss…”

mentioning

confidence: 99%

See 4 more Smart Citations

Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia

et al. 2021

Self Cite

View full text Add to dashboard Cite

Dual orexin receptor antagonists (DORAs) represent a novel type of sleep medication that provide an alternative to the traditionally used positive allosteric gamma-aminobutyric acid (GABA)-A receptor modulators. Daridorexant is a new DORA that exhibited in phase 3 trials in insomnia not only a beneficial effect on sleep variables, measured objectively and assessed subjectively, but also an improvement in daytime functioning. Daridorexant was discovered through a tailored research program aimed at identifying an optimized sleep-promoting molecule with pharmacokinetic properties appropriate for covering the whole night while avoiding next-morning residual activity at efficacious doses. By specific binding to both orexin receptors, daridorexant inhibits the actions of the wake-promoting orexin (also called hypocretin) neuropeptides. This mechanism avoids a more widespread inhibition of neuronal pathways and associated side effects that are intrinsic to positive allosteric GABA-A receptor modulators. Here, we review the general pharmacology of daridorexant, based on nonclinical pharmacology studies of daridorexant, unpublished or already described, or based on work with other DORAs. Some unique features of daridorexant will be highlighted, such as the promotion of natural and surmountable sleep, the preservation of memory and cognition, the absence of tolerance development or risk of physical dependence, and how it can benefit daytime functioning.

show abstract

Section: Promotion Of Sleep By Daridorexant Depends On Time Of the Day Sleep Pressure And Orexin Levelsmentioning

confidence: 99%

Section: Preservation Of Cognition and Memorymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

CYP3A4 Catalyzes the Rearrangement of the Dual Orexin Receptor Antagonist Daridorexant to 4‐Hydroxypiperidinol Metabolites

et al. 2023

Self Cite

View full text Add to dashboard Cite

The dual orexin receptor antagonist daridorexant was approved in 2022 in the USA and EU for the treatment of insomnia. The purpose of this study was the identification of its metabolic pathways and the human cytochrome P450 (P450) enzymes involved in its biotransformation. With human liver microsomes, daridorexant underwent hydroxylation at the methyl group of the benzimidazole moiety, oxidative O‐demethylation of the anisole to the corresponding phenol, and hydroxylation to a 4‐hydroxy piperidinol derivative. While the chemical structures of the benzylic alcohol and the phenol proved to be products of standard P450 reactions, 1D and 2D NMR data of the latter hydroxylation product was incompatible with the initially postulated hydroxylation of the pyrrolidine ring and suggested the disappearance of the pyrrolidine ring and formation of a new 6‐membered ring. Its formation is best explained by initial hydroxylation of the pyrrolidine ring in 5‐position to yield a cyclic hemiaminal. Hydrolytic ring opening then results in an aldehyde that subsequently cyclizes onto one of the benzimidazole nitrogen atoms to yield the final 4‐hydroxy piperidinol. The proposed mechanism was substantiated using an N‐methylated analogue, which might hydrolyze to the open‐chain aldehyde but cannot undergo the final cyclization step. CYP3A4 was the major P450 enzyme responsible for daridorexant metabolism, accounting for 89 % of metabolic turnover.

show abstract

Large‐Scale Synthesis of 4‐Methyl‐2‐(2H‐1,2,3‐triazol‐2‐yl)benzoic Acid – A Key Fragment of Single Orexin Receptor Antagonist ACT‐539313 – through Cu₂O‐Catalyzed, Ligand‐Free Ullmann–Goldberg Coupling

Schäfer

Fleischer

2022

Helvetica Chimica Acta

View full text Add to dashboard Cite

A vastly improved 2nd generation process for the large scale manufacturing of 4‐methyl‐2‐(2H‐1,2,3‐triazol‐2‐yl)benzoic acid (1) through an Ullmann–Goldberg coupling from 2‐bromo‐4‐methylbenzoic acid and 1H‐1,2,3‐triazole has been developed. The new process features several key process improvements compared to the original process: 1) MeCN was found as new reaction solvent, replacing the previously used undesired 1,4‐dioxane, 2) the CuI/DMCHDA catalyst system was successfully replaced by inexpensive Cu2O in the absence of any ligand, 3) the amounts of 1H‐1,2,3‐triazole and K2CO3 were both drastically decreased compared to the original route, 4) the potassium salt of the desired N2‐isomer directly crystallized from the reaction mixture and was isolated by filtration. The more soluble, undesired N1‐isomer potassium salt was purged into the mother liquor. 5) After dissolution of the N2‐isomer potassium salt in H2O and acidification with aq. HCl, the free carboxylic acid 1 crystallized as a white, crystalline solid in 61 % yield (200 g scale) and excellent HPLC purity (99.8 % a/a).

show abstract

The Quest for the Best Dual Orexin Receptor Antagonist (Daridorexant) for the Treatment of Insomnia Disorders

Cited by 31 publications

References 55 publications

Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia

Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia

CYP3A4 Catalyzes the Rearrangement of the Dual Orexin Receptor Antagonist Daridorexant to 4‐Hydroxypiperidinol Metabolites

Large‐Scale Synthesis of 4‐Methyl‐2‐(2H‐1,2,3‐triazol‐2‐yl)benzoic Acid – A Key Fragment of Single Orexin Receptor Antagonist ACT‐539313 – through Cu₂O‐Catalyzed, Ligand‐Free Ullmann–Goldberg Coupling

Contact Info

Product

Resources

About

The Quest for the Best Dual Orexin Receptor Antagonist (Daridorexant) for the Treatment of Insomnia Disorders

Cited by 31 publications

References 55 publications

Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia

Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia

CYP3A4 Catalyzes the Rearrangement of the Dual Orexin Receptor Antagonist Daridorexant to 4‐Hydroxypiperidinol Metabolites

Large‐Scale Synthesis of 4‐Methyl‐2‐(2H‐1,2,3‐triazol‐2‐yl)benzoic Acid – A Key Fragment of Single Orexin Receptor Antagonist ACT‐539313 – through Cu2O‐Catalyzed, Ligand‐Free Ullmann–Goldberg Coupling

Contact Info

Product

Resources

About

Large‐Scale Synthesis of 4‐Methyl‐2‐(2H‐1,2,3‐triazol‐2‐yl)benzoic Acid – A Key Fragment of Single Orexin Receptor Antagonist ACT‐539313 – through Cu₂O‐Catalyzed, Ligand‐Free Ullmann–Goldberg Coupling