Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system

Ijiro, Tomoyuki; Nakamura, Kayo; Ogata, Masao; Inada, Hiroyuki; Kiguchi, Sumiyoshi; Maruyama, Kazuyasu; Nabekura, Junichi; Kobayashi, Mamoru; Ishibashi, Hiroyuki

doi:10.1016/j.ejphar.2015.05.047

Cited by 14 publications

(23 citation statements)

References 52 publications

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“…Researchers have synthesized metabolically stable and more potent selective TRH prodrugs and analogs – taltirelin [TA-0910], montirelin [CG-3703], azetirelin [YM-14673], JTP-2942, DN 1417, MK-771, and posatirelin [RGH-2202] – which have potential applications in various diseases, such as depression, epilepsy, spinocerebellar degeneration, amyotrophic lateral sclerosis, Parkinson’s disease, schizophrenia, Alzheimer’s disease, and cancer-related fatigue 62. Rovatirelin is another TRH analog that binds to TRH receptor with greater affinity than taltirelin (a drug approved for spinocerebellar degeneration treatment) and has increased noradrenergic activity and increased locomotor activity 63. JAK4D binds to a new TRH receptor subtype in human hippocampal tissue and reduced cognitive defects in rat model of neurodegeneration; it also protected against neuronal damage 64.…”

Section: New Developments and Future Therapiesmentioning

confidence: 99%

New developments in the management of narcolepsy

Abad

Guilleminault

2017

NSS

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Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%–0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy’s strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss. Current treatment modalities alleviate the main symptoms of excessive daytime somnolence (EDS) and cataplexy and, to a lesser extent, reduce nocturnal sleep disruption, hypnagogic hallucinations, and sleep paralysis. Sodium oxybate (SXB), a sodium salt of γ hydroxybutyric acid, is a first-line agent for cataplexy and EDS and may help sleep disruption, hypnagogic hallucinations, and sleep paralysis. Various antidepressant medications including norepinephrine serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants are second-line agents for treating cataplexy. In addition to SXB, modafinil and armodafinil are first-line agents to treat EDS. Second-line agents for EDS are stimulants such as methylphenidate and extended-release amphetamines. Emerging therapies include non-hypocretin-based therapy, hypocretin-based treatments, and immunotherapy to prevent hypocretin neuronal death. Non-hypocretin-based novel treatments for narcolepsy include pitolisant (BF2.649, tiprolisant); JZP-110 (ADX-N05) for EDS in adults; JZP 13-005 for children; JZP-386, a deuterated sodium oxybate oral suspension; FT 218 an extended-release formulation of SXB; and JNJ-17216498, a new formulation of modafinil. Clinical trials are investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA) modulation with GABAA receptor agonists clarithromycin and flumazenil may help daytime somnolence. Other drugs investigated include GABAB agonists (baclofen), melanin-concentrating hormone antagonist, and thyrotropin-releasing hormone agonists. Hypocretin-based therapies include hypocretin peptide replacement administered either through an intracerebroventricular route or intranasal route. Hypocretin neuronal transplant and transforming stem cells into hypothalamic neurons are also discussed in this article. Immunotherapy to prevent hypocretin neuronal death is reviewed.

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Section: New Developments and Future Therapiesmentioning

confidence: 99%

New developments in the management of narcolepsy

Abad

Guilleminault

2017

NSS

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“…In vitro binding activities of TRH and 79 for human TRH-R have been reported previously. 56 The K i values of TRH and 79 for human TRH-R are 128 and 702 nM, respectively. As the human TRH-R is more similar to TRH-R1 than TRH-R2, 12 , 13 the effect of TRH analogues may be related to TRH-R1 in human.…”

Section: Resultsmentioning

confidence: 99%

Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate)

et al. 2018

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We have explored orally effective thyrotropin-releasing hormone (TRH) mimetics, showing oral bioavailability and brain penetration by structure–activity relationship (SAR) study on the basis of in vivo antagonistic activity on reserpine-induced hypothermia in mice. By primary screening of the synthesized TRH mimetics, we found a novel TRH mimetic: l-pyroglutamyl-[3-(thiazol-4-yl)-l-alanyl]-l-prolinamide with a high central nervous system effect compared with TRH as a lead compound. Further SAR optimization studies of this lead compound led to discovery of a novel orally effective TRH mimetic: 1-{N-[(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine trihydrate (rovatirelin hydrate), which was selected as a candidate for clinical trials.

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“…Mechanistically, as a TRH analogue, rovatirelin can improve motor function by increasing various neurotransmitter levels9 and having a neuroprotective effect 24. In fact, in a pharmacological study in rats, rovatirelin increased locomotor activity associated with increased noradrenaline concentration,14 as a result of its rapid absorption, stability in plasma and transition into the brain 15. Further investigation is necessary to examine whether rovatirelin can inhibit the progression of SCD with long-term treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Rovatirelin is a new TRH analogue,13 which showed higher affinity for human TRH receptors and greater absorption and transition into and stability in the brain than the existing TRH analogue, taltirelin 14 15. The effects of rovatirelin on the ataxic rolling Nagoya mice, which carry a mutation in the CACNA1A gene, were more potent and lasted longer than those of taltirelin (data on file).…”

Section: Introductionmentioning

confidence: 96%

Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials

Nishizawa

Onodera

Hirakawa

et al. 2020

J Neurol Neurosurg Psychiatry

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ObjectiveTo investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD).MethodsTwo multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with predominant cerebellar ataxia, including SCA6, SCA31 or cortical cerebellar atrophy. KPS1301 enrolled patients with truncal ataxia and KPS1305 enrolled patients with truncal and limb ataxia. Each study included 4 weeks of pretreatment, a 28-week or 24-week treatment period and 4 weeks of follow-up. Patients were randomised (1:1:1) to rovatirelin (1.6 or 2.4 mg) or placebo in KPS1301, and randomised (1:1) to rovatirelin 2.4 mg or placebo in KPS1305. The primary endpoint was change in Scale for the Assessment and Rating of Ataxia (SARA) total scores. Pooled analysis was performed in patients who met the SARA recruitment criteria of KPS1305.ResultsFrom October 2013 to May 2014, KPS1301 enrolled 411 patients; 374 were randomised to rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or placebo (n=123). From November 2016 to August 2017, KPS1305 enrolled 241 patients; 203 were randomised to rovatirelin 2.4 mg (n=101) or placebo (n=102). The primary endpoint showed no significant difference between rovatirelin and placebo in these two studies. In the pooled analysis (n=278), the difference between rovatirelin 2.4 mg (n=140) and placebo (n=138) was –0.61 (–1.64 vs –1.03; 95% CI –1.16 to –0.06; p=0.029) in the adjusted mean change in the SARA total score.ConclusionsRovatirelin is a potentially effective treatment option for SCD.Trial registration numberNCT01970098; NCT02889302

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Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system

Cited by 14 publications

References 52 publications

New developments in the management of narcolepsy

New developments in the management of narcolepsy

Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate)

Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials

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