Sleep modulating agents

Choi, Younggi; Raymer, Brian

doi:10.1016/j.bmcl.2019.06.043

Cited by 6 publications

(7 citation statements)

References 152 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nlinked pyrazole analogue 17 and N-linked [1,2,3]-triazole 18, both exhibiting a lower clogP of around 2, were not well tolerated by the OXRs. The N-linked [1,2,4]-triazole 19 had an interesting clogP value of 2.2 and showed low intrinsic clearance in HLM (CL int = 43), but its OX 1 R preference was not of interest to us. Most promising seemed [1,2,4]-triazole 20 with an OX 2 R preferential profile, a rather low intrinsic clearance in HLM of 32 and a clogP (2.6).…”

Section: Full Papersmentioning

confidence: 97%

“…Based on these promising data for triazole derivative 21, we resumed SAR studies of the aromatic moieties (Tables 3 and 4) keeping the [1,2,4]-triazole constant.…”

Section: Full Papersmentioning

confidence: 99%

“…Merck pre-coated thin layer chromatography (TLC) plates were used for TLC analysis. 1 H NMR and 13 C NMR spectra were recorded on a Bruker (400 or 500 MHz) spectrometer in the indicated deuterated solvent. Chemical shifts are reported in ppm relative to solvent peaks as the internal reference.…”

Section: Synthesismentioning

confidence: 99%

“…LC-MS B: t R = 0.38 min; [M + H] + = 216.30. 1 Step 3: TBTU (55.8 mg, 0.174 mmol) was added to a RT solution of 43 a (29 mg, 0.15 mmol), DIPEA (74 μL, 0.43 mmol) in DMF (1 mL). After 5 min at RT, 52 (31 mg, 0.15 mmol) was added and the reaction mixture was stirred at RT for 18 h. The mixture was directly purified by preparative HPLC (Method F), followed by preparative TLC (EtOAc/heptane 9 : 1) to yield 9 (37 mg, 64 %) as a white foam.…”

Section: (5-methyl-2-[123]triazol-2-yl-phenyl)-[(s)-2-(5-phenyl-[1mentioning

confidence: 99%

“…Insomnia is a sleep disorder defined by difficulties in initiating or maintaining sleep or when the sleep that is obtained is non‐refreshing or of poor quality. Current standard insomnia medications are benzodiazepines or gamma‐amino‐butyric acid (GABA) modulators, both associated with negative side effects. A mechanistically unique sleep medication is suvorexant ( 1 ) (Figure ), a dual orexin receptor antagonist (DORA).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

et al. 2020

View full text Add to dashboard Cite

The orexin system is responsible for regulating the sleep‐wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5‐methoxy‐4‐methyl‐2‐[1,2,3]triazol‐2‐yl‐phenyl)‐{(S)‐2‐[5‐(2‐trifluoromethoxy‐phenyl)‐[1,2,4]oxadiazol‐3‐yl]‐pyrrolidin‐1‐yl}methanone (6), a compound which emerged from our in‐house research program. Compound 6 was shown to be a potent, brain‐penetrating DORA with in vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above‐mentioned shortcomings resulted in the identification of (4‐chloro‐2‐[1,2,3]triazol‐2‐yl‐phenyl)‐{(S)‐2‐methyl‐2‐[5‐(2‐trifluoromethoxy‐phenyl)‐4H‐[1,2,4]triazol‐3‐yl]‐pyrrolidin‐1‐yl}l‐methanone (42), a DORA with improved in vivo efficacy compared to 6.

show abstract

Section: Full Papersmentioning

confidence: 97%

“…Based on these promising data for triazole derivative 21, we resumed SAR studies of the aromatic moieties (Tables 3 and 4) keeping the [1,2,4]-triazole constant.…”

Section: Full Papersmentioning

confidence: 99%

Section: Synthesismentioning

confidence: 99%

Section: (5-methyl-2-[123]triazol-2-yl-phenyl)-[(s)-2-(5-phenyl-[1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

et al. 2020

View full text Add to dashboard Cite

show abstract

Synthetic Methodology, SAR and Pharmacology of Commercialized Preparations Employing 1, 2, 4‐Triazole Analogues

Singh,

Kaira,

Dey

et al. 2024

ChemistrySelect

View full text Add to dashboard Cite

The domain of medicinal chemistry has witnessed a notable surge of interest in triazoles owing to their unique structural characteristics and wide range of applications. The versatility of their synthesis methods has facilitated the creation of compound libraries with remarkable pharmacological activities, including antiviral, antiepileptic, anxiolytic, hypnotic/sedatives anticancer, antifungal, and antidepressant activities. Several techniques have been documented in the literature for generating 1,2,4‐triazole derivatives. The mechanisms governing the pharmacological effects of the formulations containing 1,2,4‐triazoles were elucidated and made clear. In addition to reviewing existing marketed formulations, this review explores emerging trends and innovations in this field. This review offers a comprehensive perspective on the importance of triazoles for influencing contemporary research, fostering innovation, and driving technological progress.

show abstract

Theory of visual attention (TVA) applied to rats performing the 5-choice serial reaction time task: differential effects of dopaminergic and noradrenergic manipulations

et al. 2022

View full text Add to dashboard Cite

Rationale Attention is compromised in many psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). While dopamine and noradrenaline systems have been implicated in ADHD, their exact role in attentional processing is yet unknown. Objectives We applied the theory of visual attention (TVA) model, adapted from human research, to the rat 5-choice serial reaction time task (5CSRTT) to investigate catecholaminergic modulation of visual attentional processing in healthy subjects of high- and low-attention phenotypes. Methods Rats trained on the standard 5CSRTT and tested with variable stimulus durations were treated systemically with noradrenergic and/or dopaminergic agents (atomoxetine, methylphenidate, amphetamine, phenylephrine and atipamezole). TVA modelling was applied to estimate visual processing speed for correct and incorrect visual perceptual categorisations, independent of motor reaction times, as measures of attentional capacity. Results Atomoxetine and phenylephrine decreased response frequencies, including premature responses, increased omissions and slowed responding. In contrast, methylphenidate, amphetamine and atipamezole sped up responding and increased premature responses. Visual processing speed was also affected differentially. Atomoxetine and phenylephrine slowed, whereas methylphenidate and atipamezole sped up, visual processing, both for correct and incorrect categorisations. Amphetamine selectively improved visual processing for correct, though not incorrect, responses in high-attention rats only, possibly reflecting improved attention. Conclusions These data indicate that the application of TVA to the 5CSRTT provides an enhanced sensitivity to capturing attentional effects. Unexpectedly, we found overall slowing effects, including impaired visual processing, following drugs either increasing extracellular noradrenaline (atomoxetine) or activating the α1-adrenoceptor (phenylephrine), while also ameliorating premature responses (impulsivity). In contrast, amphetamine had potential pro-attentional effects by enhancing visual processing, probably due to central dopamine upregulation.

show abstract

Sleep modulating agents

Cited by 6 publications

References 152 publications

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

From Oxadiazole to Triazole Analogues: Optimization toward a Dual Orexin Receptor Antagonist with Improved in vivo Efficacy in Dogs

Synthetic Methodology, SAR and Pharmacology of Commercialized Preparations Employing 1, 2, 4‐Triazole Analogues

Theory of visual attention (TVA) applied to rats performing the 5-choice serial reaction time task: differential effects of dopaminergic and noradrenergic manipulations

Contact Info

Product

Resources

About