Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders

Fabio, Romano Di; Pellacani, Annalisa; Faedo, Stefania; Roth, Adelheid; Piccoli, Laura; Gerrard, Philip; Porter, Rod A.; Johnson, Christopher N.; Thewlis, Kevin M.; Donati, Daniele; Stasi, Luigi; Spada, Simone; Stemp, Geoffrey; Nash, David J.; Branch, Clive L.; Kindon, Leanda; Massagrande, Mario; Poffe, Alessandro; Braggio, Simone; Chiarparin, Elisabetta; Marchioro, Carla; Ratti, Emiliangelo; Corsi, Mauro

doi:10.1016/j.bmcl.2011.06.086

Cited by 51 publications

(50 citation statements)

References 28 publications

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“…On the contrary, the OX 1 R antagonist GSK1059865 showed a very poor hypnotic ability to induce and maintain sleep. These findings are in keeping with other reports suggesting that OX 2 R might be more important than OX 1 R in mediating the OX effect on sleep (Sakurai, 2007;Brisbare-Roch et al, 2007;Malherbe et al, 2009;Dugovic et al, 2009;Di Fabio et al, 2011).…”

Section: Discussionsupporting

confidence: 93%

“…Finally, the compounds were tested at the defined doses in the BE model. OX 1 R and OX 2 R antagonists are reported in the literature to be involved in the control of sleep, in particular to induce hypnotic effects (Di Fabio et al, 2011;Gozzi et al, 2011;Dugovic et al, 2009). In a preclinical hypnotic sleep model in male rats, the results obtained demonstrated that the dual OX 1 /OX 2 R antagonist, SB-649868, induced a robust hypnotic effect, both on the ability to induce and to maintain sleep, reaching a statistically significant effect at 3 mg/kg.…”

Section: Discussionmentioning

confidence: 91%

“…Moreover, the simultaneous antagonism of both OX 1 R and OX 2 R or the selective inhibition of OX 2 R results in the induction of a strong hypnotic effect (Brisbare-Roch et al, 2007;Dugovic et al, 2009;Di Fabio et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, this study was aimed at investigating the effect of the dual OX 1 /OX 2 R antagonist SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide) (Di Fabio et al, 2011), the selective OX 1 R antagonist GSK1059865 (5-bromo-N-[(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine) (Gozzi et al, 2011), and the selective OX 2 R antagonist JNJ-10397049 (N-(2,4-dibromophenyl) (McAtee et al, 2004;Dugovic et al, 2009) in the BE model described by Cifani et al (2009), in which BE episodes for HPF is evoked in female rats by cycles of food restriction/re-feeding and acute stress. The three antagonists were first evaluated in vitro in rat recombinant OX 1 R and OX 2 R to determine their potency and to confirm their selectivity for the two receptor subtypes.…”

Section: Introductionmentioning

confidence: 99%

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Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Piccoli

Bonaventura

Cifani

et al. 2012

Neuropsychopharmacol

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144

102

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Orexins (OX) and their receptors (OXR) modulate feeding, arousal, stress, and drug abuse. Neural systems that motivate and reinforce drug abuse may also underlie compulsive food seeking and intake. Therefore, the effects of GSK1059865, a dual OX 1 /OX 2 R antagonist were evaluated in a binge eating (BE) model in female rats. BE of highly palatable food (HPF) was evoked by three cycles of food restriction followed by stress, elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Pharmacokinetic assessments of all compounds were obtained under the same experimental conditions used for the behavioral experiments. Topiramate was used as the reference compound as it selectively blocks BE in rats and humans. Dose-related thresholds for sleep-inducing effects of the OXR antagonists were measured using polysomnography in parallel experiments. SB-649868 and GSK1059865, but not JNJ-10397049, selectively reduced BE for HPF without affecting standard food pellet intake, at doses that did not induce sleep. These results indicate, for the first time, a major role of OX 1 R mechanisms in BE, suggesting that selective antagonism at OX 1 R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Piccoli

Bonaventura

Cifani

et al. 2012

Neuropsychopharmacol

Self Cite

144

102

View full text Add to dashboard Cite

show abstract

“…SB-649868 was reported to inhibit both OX 1 and OX 2 receptor activity and entered clinical trials in 2005. Preclinically, SB-649868 was shown to be sleeppromoting in rodent and primate studies (Di Fabio et al, 2011). In 2007, GSK announced that SB-649868 had advanced to phase II clinical trials.…”

Section: B Dual Orexin Receptor Antagonistsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

et al. 2012

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Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Mei

Han

White

et al. 2020

Chemistry A European J

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Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor‐made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man‐made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

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Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders

Cited by 51 publications

References 28 publications

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

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