Orexin receptor antagonists – a patent review (2010 to August 2014)

  title={Orexin receptor antagonists – a patent review (2010 to August 2014)},
  author={Christoph Boss},
  journal={Expert Opinion on Therapeutic Patents},
  pages={1367 - 1381}
  • C. Boss
  • Published 19 November 2014
  • Biology, Psychology
  • Expert Opinion on Therapeutic Patents
Introduction: The orexin (hypocretin) system is an evolutionarily conserved neuropeptide-G-protein-coupled receptor system, consisting of two neuropeptides the orexin-A and the orexin-B peptides as well as two receptors the orexin-1 and the orexin-2 receptors. The orexin system is crucially involved in the regulation of the circadian rhythm, states of wakefulness and arousal and the modulation of emotions and has attracted the interest of many researchers which resulted in an enormous amount of… 

Orexin research: patent news from 2016

  • C. BossC. Roch
  • Biology, Psychology
    Expert opinion on therapeutic patents
  • 2017
The patent applications from Thomson Reuters Integrity Database added in 2016 are summarized and discussed together with the most important findings published in the scientific literature to show the continuing interest in the orexin receptors as targets.

An overview of the orexinergic system in different animal species.

This review highlights the distinct variabilities in the morphophysiological aspects of the orexinergic system in the vertebrate animals, mammals and non-mammals, its presence in other brain-related structures, including its involvement in ageing and neurodegenerative diseases.

Substituted cyclopentanes, tetrahydrofurans and pyrrolidines as orexin-1-receptor antagonists for treatment of various CNS disorders (WO2015/055994; WO2015/124932; WO2015/124934)

Structurally, the building blocks used to prepare the compounds are reminiscent of other orexin antagonist programs recently disclosed in the literature, however, the templates used are novel in the orexIn antagonist field and are probably the key feature for the selectivity of the derivatives towards the Orexin-1 receptor.

Discovery of HTL6641, a dual orexin receptor antagonist with differentiated pharmacodynamic properties

A novel series of potent, selective, and orally efficacious dual antagonists of the orexin receptors has been investigated, resulting in the identification of lead compound 27 (HTL6641), having a short dissociation half-life.

1,2-Benzisoxazole compounds: a patent review (2009 – 2014)

  • Y. Uto
  • Chemistry
    Expert opinion on therapeutic patents
  • 2015
This review puts emphasis on the recent progress in therapeutically attractive benzisoxazole derivatives especially 1,2-benzis oxazoles, which were published in the patent literature between 2009 and 2014, and the main focus is on atypical antipsychotics and potential therapeutic treatments for other CNS disorders.

Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist.

The design, synthesis, characterization, and structure-activity relationships (SARs) of novel orexin receptor antagonists are reported and various modifications made to the core structure of a previously developed compound resulted in compounds with improved chemical and pharmacological profiles.

Arcuate Nucleus Orexin-A Signaling Alleviates Cisplatin-Induced Nausea and Vomiting Through the Paraventricular Nucleus of the Hypothalamus in Rats

A novel neurobiological circuit from the ARC to the PVN that might provide a potential target for the prevention and treatment of cisplatin-induced nausea and vomiting is revealed.

Orexin A and Central Precocious Puberty

Maternally expressed gene 3 (MEG3) is an imprinted long non-coding RNAs (LncRNAs) which is highly expressed in the brain and pituitary gland, which may involve in pituitaries hyperplasia of CPP.

Functional characterization of an orexin neuropeptide in amphioxus reveals an ancient origin of orexin/orexin receptor system in chordate

It is demonstrated that a functional orexin neuropeptide has already emerged in amphioxus, which provide insights into the evolutionary origin of Orexin in chordate and the functional homology between the cerebral vesicle and vertebrate brain.



Biomedical application of orexin/hypocretin receptor ligands in neuroscience.

Orexin/hypocretin neuropeptides are peptides discovered and published in 1998 by two independent research groups as the outcome of methodical deorphanization programs focusing on brain orphan G-protein-coupled receptors (GPCR).

Orexin Receptor Antagonists: A New Concept In CNS Disorders?

It appears that the orexin system plays a crucial role as homeostatic sensor of the body’s external and internal environment and regulates states of wakefulness to facilitate survival.

Discovery and development of orexin receptor antagonists as therapeutics for insomnia

Based on the publication of recent non‐clinical and clinical data, orexin receptor antagonists potentially represent a targeted, effective and well‐tolerated new class of medications for insomnia.

Structure–Activity Relationship, Biological, and Pharmacological Characterization of the Proline Sulfonamide ACT‐462206: a Potent, Brain‐Penetrant Dual Orexin 1/Orexin 2 Receptor Antagonist

ACT‐462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the Orexin peptides at both the orexIn’1 and 2 receptors, and shows anxiolytic‐like properties in rats without affecting cognition and motor function, making it a potential candidate for the treatment of insomnia.

Almorexant, a dual orexin receptor antagonist for the treatment of insomnia.

  • D. Neubauer
  • Psychology, Biology
    Current opinion in investigational drugs
  • 2010
The use of an orexin receptor antagonist for the treatment of sleep disorders appears to be an approach that may provide unique benefits, and reported efficacy and safety data for almorexant support the continued development of the compound.

Discovery of MK-3697: a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia.

Evidence implicating a role for orexin-1 receptor modulation of paradoxical sleep in the rat

Orexin: a link between energy homeostasis and adaptive behaviour.

  • T. Sakurai
  • Biology, Psychology
    Current opinion in clinical nutrition and metabolic care
  • 2003
Orexin neurons have the requisite functional interactions with hypothalamic feeding pathways and monoaminergic-cholinergic centres in the brain stem, and regulation by nutritional factors, to suggest that they may be an important cellular link in the integration of adaptive behaviour associated with arousal and energy homeostasis.

Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis.

The hypothalamic peptides, orexin-A and orexin-B, have been implicated in the regulation of feeding behavior. In starved rats catabolic activity quickly predominates, reinforced by elevated

Blockade of Orexin-1 Receptors Attenuates Orexin-2 Receptor Antagonism-Induced Sleep Promotion in the Rat

Results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system.