Design, synthesis and in vitro evaluation of bridgehead fluoromethyl analogs of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) for the 5-HT1A receptor

Hussainy, R. al; Verbeek, Joost; Born, Dion van der; Booij, Jan; Herscheid, J. D. M.

doi:10.1016/j.ejmech.2011.06.023

Cited by 24 publications

(15 citation statements)

References 34 publications

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“…One study examined the effects of bridgehead fluoromethyl group (cubyl, adamantly and others) with some success (Al Hussainy et al, 2011). RWAY- which contains a cycloheptyl has been studied with 11 C-RWAY, although human studies have indicated interference by a lipophilic metabolite (Zhang et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of mefway analogs as ligands for serotonin 5HT1A receptors

et al. 2014

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18F-Mefway (N-{2-[4-(2′-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4′-18F-fluoro-methylcyclohexane)carboxamide) was developed and evaluated for use as a PET ligand for imaging 5-HT1A receptors. Ongoing studies of 18F-Mefway have shown it to be an effective PET radiotracer. We have synthesized isomers of Mefway by changing the position of the methyl-group in attempts to evaluate stability for imaging purposes. 2-Methyl-, 3-methyl-, and 4-methyl-cyclohexane-1-carboxylic acids and 3-carbomethoxy-, 4-carbomethoxycyclohexane-1-carboxylic acids were coupled with WAY-100634 to provide the methylcyclohexyl derivatives (2-, 3- and 4-methyl). Mefway and 3-Mefway analogs were prepared by reduction of carbomethoxy-derivatives followed by fluorination. In vitro binding affinities for the methylated derivatives in rat brain homogenates was found to be 10.4 nM (2-methyl), 77 nM (3-methyl) and 21.5 nM (4-methyl). Binding affinity of 3-Mefway and 4-Mefway was found to be 17.4 nM and 6.26 nM, respectively. Our results suggest that 3-methyl/3-fluoromethyl substituent has approx. 3-fold lower affinities compared to the 4-methyl/4-fluoromethyl substituent.

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Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of mefway analogs as ligands for serotonin 5HT1A receptors

et al. 2014

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“…For this goal, compounds 78 were synthesized, including the 18 F tracers for imaging. 88,89 In rats, all three compounds showed a higher uptake in the hippocampus and cortex, regions where the 5-HT 1A receptor would be expected. Compound 78a showed slightly higher uptake in the liver than 78b, which was explained by the enhanced hepatic processing of the cubyl moiety.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 96%

“…69 Radiolabeled compound 64 ( 123 I) was developed as a probe for in vivo Staudinger ligation to azide tagged antibodies. 70 In comparison to desferrioxamine type probes with 89 Zr or 67/68 Ga radiolabeling, compound 64 showed poor pharmacokinetics and thus was not explored further in this study. As a way to improve upon compound 14a for inhibition of monoamine oxidase B, the series of compounds 14b,c were synthesized.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Cubanes in Medicinal Chemistry

2018

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Cubane is a highly strained saturated hydrocarbon system that has historically been of interest in theoretical organic chemistry. More recently it has become a molecule of interest for biological applications due to its inherent stability and limited toxicity. Of greater significance is the ability to potentially functionalize cubane at each of its carbon atoms, providing complex biologically active molecules with unique spatial arrangements for probing active sites. These characteristics have led to an increased use of cubane in pharmaceutically relevant molecules. In this Perspective we describe synthetic methodology for accessing a range of functionalized cubanes and their applications in pharmaceuticals. We also provide some perspectives on challenges and future directions in the advancement of this field.

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“…We also thank the Ministry of Higher Education (Malaysia) for funding structural studies through the High-Impact Research scheme (UM.C/HIR/MOHE/SC/12). Hussainy et al, 2011;Moussa et al, 2011), anti-convulsant (Kamiński et al, 2011, anti-microbial (Sheng et al, 2011), anti-cancer (Yang et al 2011) and histamine antagonist (Liu et al, 2011). In continuation of our interest in the chemical and pharmacological properties of 1,4-piperazine derivatives (Kadi et al, 2010), we synthesized the title compound, (I), as an intermediate for potential chemotherapeutic agents.…”

Section: Crystal Datamentioning

confidence: 99%