Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists

Stasi, Luigi; Artusi, Roberto; Bovino, Clara; Buzzi, Benedetta; Canciani, Luca; Caselli, Gianfranco; Colace, F; Garofalo, Paolo; Giambuzzi, Silvia; Larger, Patrice; Letari, Ornella; Mandelli, Stefano; Perugini, Lorenzo; Pucci, Sabrina; Salvi, Matteo; Toro, PierLuigi

doi:10.1016/j.bmcl.2013.02.093

Cited by 11 publications

(6 citation statements)

References 16 publications

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“…As illustrated in Figure 3, some of these compounds (e.g. 14 and 15) possessed good OX1 potency and high selectivity (> 100-fold) (Stasi et al, 2013;Stasi & Rovati, 2011). The Scripps Research Institute (TSRI) Florida group reported hexahydrocyclopenta[c]pyrrole analogs.…”

Section: Pyrrolidinesmentioning

confidence: 99%

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Therapeutics development for addiction: Orexin-1 receptor antagonists

Perrey

Zhang

2020

Brain Research

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The orexin system includes the neuropeptides orexin A and B and the cognate receptors of orexin-1 (OX1) and -2 (OX2) and has been indicated in a number of important physiological processes. It is generally accepted that the OX1 receptor is mainly involved in motivation and reward and the OX2 receptor in the modulation of sleep/wake cycle and energy homeostasis. A variety of OX1 selective antagonists (1-SORAs) have been disclosed in the literature and some of them have been evaluated as potential therapeutics for addiction treatment. In this review we summarize all OX1 antagonists reported thus far based on their core structure. Several dual orexin receptor antagonists (DORAs) and OX2 selective antagonist (2-SORAs) have also been recently evaluated in reward and addiction models. While DORAs may seem pharmacologically advantageous for alcohol addiction given the recent findings on the OX2 receptor in reward and alcohol consumption, 1-SORAs are the better options for other drugs of addiction such as cocaine due to the absence of the sedative effects inherently associated with dual antagonists.

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Section: Pyrrolidinesmentioning

confidence: 99%

“…Rottapharm Madaus reported a series of azaspiro compounds (e.g. 31) (Stasi et al, 2013;Stasi & Rovati, 2011), and GSK described a variety of azabicylco[4.1.0]heptanes (e.g. 32) (Alvaro et al, 2010).…”

Section: Other Piperidine-like Analogsmentioning

confidence: 99%

Therapeutics development for addiction: Orexin-1 receptor antagonists

Perrey

Zhang

2020

Brain Research

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“…Additionally, Rottapharm Madaus has reported a series of azaspiro compounds as selective OX 1 antagonists, and identified the spiro moiety as a key structural feature for OX 1 receptor selectivity. 29,30 Several other OX 1 selective antagonists have also been reported, including GSK-1059865 and its analogs, as well as ACT-335827, although these compounds mostly retained a significant amount of OX 2 activity. [31][32][33] Our group has been developing OX 1 selective antagonists for the potential treatment of drug addiction and related disorders.…”

Section: Introductionmentioning

confidence: 99%

“…The 3-nitro analog (26) showed ~7-fold reduced potency, whereas dimethylamino analog 28 gave a significant improvement of potency at the OX 1 receptor (Ke = 13 nM) but also increased the OX 2 receptor potency. However, larger N-alkyl groups were not as well tolerated and the potency decreased with the increase of the size of the alkyl groups (29)(30)(31)(32)(33), with the benzyl analog (33) having no activity at concentrations up to 10 μM. Interestingly, while the acetyl derivatives 34 had a significant drop in potency, 35, which had a larger acyl group, regained most of the potency.…”

Section: Introductionmentioning

confidence: 99%

The effect of 1-substitution on tetrahydroisoquinolines as selective antagonists for the Orexin-1 receptor

Zhang

Perrey

German

et al. 2015

Drug and Alcohol Dependence

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Selective blockade of the Orexin-1 receptor has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX 1 selective antagonists. Aimed at elucidating SAR requirements in other regions of the molecule and further enhancing OX 1 potency and selectivity, we have designed and synthesized a series of analogs bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX 1 receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX 1 receptor and >620-fold selectivity over the OX 2 receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats.

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“…Therefore, determination of drug metabolism and pharmacokinetic properties are crucial in the drug research process (Alavijeh & Palmer, 2004;Caldwell, Ritchie, Masucci, Hageman, & Yan, 2001;Hsieh et al, 2009;Singh, 2006;Tuntland et al, 2014;Thompson, 2000;Yengi, Leung, & Kao, 2007). They are important factors in deciding the fate of a drug in the clinic (Stasi et al, 2013). Thus, considering the growing beneficial role of anemoside B4 for antiviral activity, pharmacokinetic, tissue distribution and excretion studies of anemoside B4 in vivo by i.p.…”

mentioning

confidence: 99%

Application of a liquid chromatography–tandem mass spectrometry method to the pharmacokinetics, tissue distribution and excretion in the study of anemoside B4, a novel antiviral agent candidate, in rats

Ouyang

et al. 2017

Biomedical Chromatography

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A simple, sensitive and reliable LC-MS/MS method was developed and validated for the quantification of anemoside B4, a potential antiviral constituent isolated from Pulsatilla chinensis in rat plasma, tissue, bile, urine and feces. All biological samples were prepared by protein precipitation method, and ginsenoside-Rg1 was chosen as the internal standard (IS). The analyte and IS were separated using a C column (2.1 × 50 mm, 1.8 μm) and a mobile phase consisting of 0.1% formic acid in water (v/v) and acetonitrile running at a flow rate of 0.2 mL/min for 5 min. The multiple reaction monitoring transitions were monitored at m/z 1219.5-749.5 for anemoside B4 and 845.4-637.4 for ginsenoside-Rg1 in electrospray ionization negative mode. The calibration curve was linear in the range of 10-2000 ng/mL for all biological matrices with a lower limit of quantification of 10 ng/mL. The validated method was successfully applied to a pharmacokinetics, tissue distribution and excretion study. These preclinical data will be beneficial for further development of anemoside B4 in future studies.

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Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists

Cited by 11 publications

References 16 publications

Therapeutics development for addiction: Orexin-1 receptor antagonists

Therapeutics development for addiction: Orexin-1 receptor antagonists

The effect of 1-substitution on tetrahydroisoquinolines as selective antagonists for the Orexin-1 receptor

Application of a liquid chromatography–tandem mass spectrometry method to the pharmacokinetics, tissue distribution and excretion in the study of anemoside B4, a novel antiviral agent candidate, in rats

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