An Orally Active, Water-Soluble Neurokinin-1 Receptor Antagonist Suitable for Both Intravenous and Oral Clinical Administration

Harrison, Timothy; Owens, Andrew; Williams, Brian J.; Swain, Christopher J.; Williams, Angela; Carlson, Emma; Rycroft, W.; Tattersall, F.D.; Cascieri, Margaret A.; Chicchi, Gary G.; Sadowski, S.; Rupniak, N. M. J.; Hargreaves, Richard

doi:10.1021/jm0109558

Cited by 51 publications

(47 citation statements)

References 13 publications

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“…The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. [126] Compound 62 was found to be highly effective in preclinical tests for emesis and depression. Stensbo and co-workers reported the synthesis and biological activity of 1-hydroxy azole derivatives.…”

Section: Antifungal and Antibacterialsmentioning

confidence: 99%

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Agalave

Maujan

Pore

2011

Chemistry An Asian Journal

1,143

508

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The copper(I)-catalyzed 1,2,3-triazole-forming reaction between azides and terminal alkynes has become the gold standard of click chemistry due to its reliability, specificity, and biocompatibility. Applications of click chemistry are increasingly found in all aspects of drug discovery; they range from lead finding through combinatorial chemistry and target-templated in vitro chemistry, to proteomics and DNA research by using bioconjugation reactions. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen-bonding and dipole interactions. The present review will focus mainly on the recent literature for applications of this reaction in the field of medicinal chemistry, in particular on use of the 1,2,3-triazole moiety as pharmacophore.

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Section: Antifungal and Antibacterialsmentioning

confidence: 99%

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Agalave

Maujan

Pore

2011

Chemistry An Asian Journal

1,143

508

View full text Add to dashboard Cite

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“…Among the agents used to alleviate these conditions are H 1 -blockers (Bergman and Spealman, 1988;Tonato et al, 1994), D 2 -blockers (Jovanovic-Micic et al, 1995;Mystakidou et al, 1998), 5-hydroxytryptamine 3 blockers (Gregory and Ettinger, 1998;Ye et al, 2001), and cannabinoids (Abrahamov et al, 1995;Mechoulam and Hanu, 2001). More recently, efforts have been made to determine the efficacy of NK 1 receptor 1 antagonists against chemotherapy-induced nausea and vomiting (Bountra et al, 1993;Tattersall et al, 1994;Beattie et al, 1995;Gardner et al, 1995Gardner et al, , 1996Harrison et al, 2001). Using the ferret, it has been established that brain penetration of NK 1 antagonists is essential to prevent drug-induced (cisplatin) emesis, and several compounds have been shown to be efficacious in this regard (Watson et al, 1995;Gonsalves et al, 1996;Rudd et al, 1996;Tattersall et al, 1996;Rupniak et al, 1997;Singh et al, 1997;Zaman et al, 2000;Harrison et al, 2001).…”

mentioning

confidence: 99%

“…More recently, efforts have been made to determine the efficacy of NK 1 receptor 1 antagonists against chemotherapy-induced nausea and vomiting (Bountra et al, 1993;Tattersall et al, 1994;Beattie et al, 1995;Gardner et al, 1995Gardner et al, , 1996Harrison et al, 2001). Using the ferret, it has been established that brain penetration of NK 1 antagonists is essential to prevent drug-induced (cisplatin) emesis, and several compounds have been shown to be efficacious in this regard (Watson et al, 1995;Gonsalves et al, 1996;Rudd et al, 1996;Tattersall et al, 1996;Rupniak et al, 1997;Singh et al, 1997;Zaman et al, 2000;Harrison et al, 2001). One of these compounds is aprepitant phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one) Tattersall et al, 2000;Harrison et al, 2001).…”

mentioning

confidence: 99%

“…Using the ferret, it has been established that brain penetration of NK 1 antagonists is essential to prevent drug-induced (cisplatin) emesis, and several compounds have been shown to be efficacious in this regard (Watson et al, 1995;Gonsalves et al, 1996;Rudd et al, 1996;Tattersall et al, 1996;Rupniak et al, 1997;Singh et al, 1997;Zaman et al, 2000;Harrison et al, 2001). One of these compounds is aprepitant phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one) Tattersall et al, 2000;Harrison et al, 2001). Aprepitant exhibited a protracted effect in blocking the cisplatininduced emesis in ferrets (Tattersall et al, 2000;Harrison et al, 2001).…”

mentioning

confidence: 99%

“…One of these compounds is aprepitant phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one) Tattersall et al, 2000;Harrison et al, 2001). Aprepitant exhibited a protracted effect in blocking the cisplatininduced emesis in ferrets (Tattersall et al, 2000;Harrison et al, 2001). This is a crucial effect because, in humans undergoing treatment with chemotherapeutic agents such as cisplatin, the nausea and vomiting may persist for many days after the initial cancer treatment (Navari et al, 1999;Campos et al, 2001;Cocquyt et al, 2001).…”

mentioning

confidence: 99%

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Brain Penetration of Aprepitant, a Substance P Receptor Antagonist, in Ferrets

Huskey¹,

Dean²,

Bakhtiar³

et al. 2003

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics, metabolism, and brain penetration of the neurokinin 1 (NK 1 ) receptor antagonist (substance P receptor antagonist), aprepitant (MK-0869), were examined in ferrets. This species exhibits human-type NK 1 receptor pharmacology and is of proven value in the identification of clinically useful drugs for the treatment of chemotherapy-induced nausea and vomiting in humans. After a single p.o. dose of aprepitant at 1 or 2 mg/kg, plasma levels of the compound were between ϳ200 and 270 ng/ml, 24 h after dosing. In the brain cortex, concentrations of aprepitant reached between ϳ80 and 150 ng/g of tissue 24 h after dosing. The predominant radioactive component present in the plasma and the brain of ferrets at 24 or 48 h after a single oral dose of [ 14 C]aprepitant at 3 mg/kg was the parent compound itself. The slow plasma clearance of aprepitant (ϳ1.5 ml/min/kg) and its abundance in ferret brain were in accord with its efficacy in blocking the retching and vomiting at 24 and 48 h postdose when ferrets were challenged with the emetic anticancer drug, cisplatin. When aprepitant and some of its metabolites were assessed for their in vitro binding affinity to the human NK 1 receptor, aprepitant demonstrated the highest affinity. Collectively, these data suggested that aprepitant, rather than its metabolites, was responsible, primarily, for the antiemetic activity of this compound in the male ferret.

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Peptidomimetics for Drug Design

Estiarte

Rich

2003

Burger's Medicinal Chemistry and Drug Discovery

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The past and present role of peptidomimetics to drug discovery and protein design is summarized. The historical evolution of this area of research and the current state‐of‐the‐art research strategies are described. A detailed description of each of the peptidomimetics types that have appeared in the literature so far is discussed. Some examples are used to illustrate the drug design process that proceeds from the native peptide to a completely non‐peptide peptidomimetic structure. Special attention is given to important pharmaceutical targets such as the cysteine, metallo, serineor aspartic proteases, integrins, G‐protein–coupled receptors, etc. The principles currently used are highlighted in the discussions of some of the most successful examples. It is obvious that major progress in this area is primarily derived of recent advances in all aspects of science. Molecular modeling, X‐ray crystallography, and high field NMR have greatly contributed to this endeavor. Peptidomimetic inhibitors were traditionally developed by modifying peptide bonds, by mimicking the transition states for enzyme‐catalyzed reactions, or by constraining the conformational mobility of a peptide‐derived chain; the latter was used to overcome some of the pharmacokinetic barriers encountered in using peptides as drugs. Lately, these difficulties have been partially solved with rational drug design of de novo compounds. Several methods have been successfully applied, with noteworthy examples currently in clinical trials, and many others are expected in the near future. It would be wrong, however, to imply that this process is a universal panacea. New ideas are urgently needed to produce clinical candidates faster and to solve some of the undesired pharmacokinetic issues.

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An Orally Active, Water-Soluble Neurokinin-1 Receptor Antagonist Suitable for Both Intravenous and Oral Clinical Administration

Cited by 51 publications

References 13 publications

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

Brain Penetration of Aprepitant, a Substance P Receptor Antagonist, in Ferrets

Peptidomimetics for Drug Design

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