Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia

Futamura, Aya; Suzuki, Ryo; Tamura, Yunoshin; Kawamoto, Hiroshi; Ohmichi, Mari; Hino, Noriko; Tokumaru, Yuichi; Kirinuki, Sora; Hiyoshi, Tetsuaki; Aoki, Takeshi; Kambe, Daiji; Nozawa, Dai

doi:10.1016/j.bmc.2020.115489

Cited by 11 publications

(21 citation statements)

References 25 publications

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“…ORN‐0829/TS‐142 [76] is a DORA nonselective for Hcrt‐R1 versus Hcrt‐R2 in functional pharmacology assays. It was designed with similar principles in mind to daridorexant, namely, the generation of a hypnotic for the treatment of insomnia with a short onset of action and a relatively short T 1/2 in humans in order to reduce next‐day side effects.…”

Section: Drug Discovery and Developmentmentioning

confidence: 99%

Hypocretins (orexins): The ultimate translational neuropeptides

2022

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The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin‐induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance‐use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit‐related neuropsychiatric and neurodegenerative conditions.

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Section: Drug Discovery and Developmentmentioning

confidence: 99%

Hypocretins (orexins): The ultimate translational neuropeptides

2022

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“…These bicyclic hemiaminal ethers proved to be very stable under acidic conditions, with no appreciable decomposition observed when incubated at pH values ranging from 1 to 10 at 40 °C for 24 h. 192 ORN0829 (421), an orexin antagonist recently identified as a clinical candidate for the treatment of insomnia, is built on a cyclic hemiaminal scaffold that has been shown to possess good chemical stability. 193 The design concept is depicted in Figure 20 and sought to introduce conformational constraint into the amide moiety of 419 by installing the piperidine heterocycle in 420, a modification that fully preserved the binding profile of the progenitor. However, replacing the piperidine ring in 420 with the cyclic aminal in 421 was sufficient to lower lipophilicity to the preferred range for CNS drugs without materially affecting antagonist potency.…”

Section: Acetals and Ketals (R−o−c−o−r′)mentioning

confidence: 99%

“…The oral bioavailability of 421 was 5.5% in the rat and 61.6% in the dog, with a peak brain concentration in rats of 2.33 nM following a 3 mpk dose, reflecting a brain to plasma ratio of 1:7. 193 An interesting and unique hemiaminal motif is found in the cephamycins, a group of β-lactam antibiotics and are structurally related to the cephalosporins. 194a The cephamycins possess an α-disposed methoxy substituent at the C7 position (426, Figure 21), which confers unusually high resistance to degradation by β-lactamases, presumably a reflection of steric hindrance of the adjacent carbonyl moiety of the β-lactam ring.…”

Section: Acetals and Ketals (R−o−c−o−r′)mentioning

confidence: 99%

“…ORN0829 ( 421 ), an orexin antagonist recently identified as a clinical candidate for the treatment of insomnia, is built on a cyclic hemiaminal scaffold that has been shown to possess good chemical stability . The design concept is depicted in Figure and sought to introduce conformational constraint into the amide moiety of 419 by installing the piperidine heterocycle in 420 , a modification that fully preserved the binding profile of the progenitor.…”

Section: Introductionmentioning

confidence: 99%

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Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design

Meanwell

2021

J. Med. Chem.

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Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.

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“…TS-142 is a novel and potent dual orexin receptor antagonist designed to have the pharmacokinetic properties of fast absorption and short plasma half-life. TS-142 has antagonist activities against human OX 1 and OX 2 with IC 50 values of 1.05 nM (OX 1 ) and 1.27 nM (OX 2 ) (Futamura et al 2020 ). In healthy adult subjects, TS-142 reached a maximum concentration within 2.50 h of administration and has an elimination half-life of 1.32—3.25 h when administered orally (Uchiyama et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study

et al. 2022

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Rationale Novel compound with potent antagonistic activity against orexin receptors may be new treatment option for patients with insomnia. Objective The aim was to investigate the efficacy and safety of single oral doses of the dual orexin receptor antagonist TS-142 in patients with insomnia. Methods This multicenter, double-blind, crossover randomized clinical trial included non-elderly patients with insomnia. Patients were randomized to receive single doses of placebo and TS-142 at doses of 5, 10, and 30 mg in one of four different sequences, with a 7-day washout period between treatments. Primary efficacy endpoints were latency to persistent sleep (LPS) and wake time after sleep onset (WASO) measured by polysomnography. Results Twenty-four patients were included (mean age 50.3 ± 10.5 years; mean duration of insomnia 5.71 ± 8.68 years). Least-squares mean differences (95% confidence interval) from placebo in LPS with 5, 10, and 30 mg TS-142 were − 42.38 (− 60.13, − 24.63), − 42.10 (− 60.02, − 24.17), and − 44.68 (− 62.41, − 26.95) minutes, respectively (all p < 0.001). Least-squares mean differences (95% confidence interval) from placebo in WASO with 5, 10, and 30 mg TS-142 were − 27.52 (− 46.90, − 8.14), − 35.44 (− 55.02, − 15.87), and − 54.69 (− 74.16, − 35.23) minutes, respectively (all p < 0.01). Self-reported aspects of sleep initiation and sleep quality, determined using the Leeds Sleep Evaluation Questionnaire (LSEQ), were also improved with TS-142 administration versus placebo. TS-142 was well tolerated; all adverse events were mild or moderate and none were serious. Conclusion Single-dose TS-142 was well tolerated and had clinically relevant effects on objective and subjective sleep parameters in patients with insomnia. Clinical Trial registration JapicCTI173570 (www.clinicaltrials.jp); NCT04573725 (www.clinicaltrials.gov).

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Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia

Cited by 11 publications

References 25 publications

Hypocretins (orexins): The ultimate translational neuropeptides

Hypocretins (orexins): The ultimate translational neuropeptides

Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design

Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study

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