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1.
Basic Clin Pharmacol Toxicol ; 128(2): 204-212, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33176395

RESUMEN

The coronavirus responsible for COVID-19, SARS-CoV-2, utilizes a viral membrane spike protein for host cell entry. For the virus to engage in host membrane fusion, SARS-CoV-2 utilizes the human transmembrane surface protease, TMPRSS2, to cleave and activate the spike protein. Camostat mesylate, an orally available well-known serine protease inhibitor, is a potent inhibitor of TMPRSS2 and has been hypothesized as a potential antiviral drug against COVID-19. In vitro human cell and animal studies have shown that camostat mesylate inhibits virus-cell membrane fusion and hence viral replication. In mice, camostat mesylate treatment during acute infection with influenza, also dependent on TMPRSS2, leads to a reduced viral load. The decreased viral load may be associated with an improved patient outcome. Because camostat mesylate is administered as an oral drug, it may be used in outpatients as well as inpatients at all disease stages of SARS-CoV-2 infection if it is shown to be an effective antiviral agent. Clinical trials are currently ongoing to test whether this well-known drug could be repurposed and utilized to combat the current pandemic. In the following, we will review current knowledge on camostat mesylate mode of action, potential benefits as an antiviral agent and ongoing clinical trials.


Asunto(s)
Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Ésteres/uso terapéutico , Guanidinas/uso terapéutico , Inhibidores de Serina Proteinasa/uso terapéutico , Animales , Antivirales/administración & dosificación , Antivirales/efectos adversos , Reposicionamiento de Medicamentos , Ésteres/administración & dosificación , Ésteres/efectos adversos , Guanidinas/administración & dosificación , Guanidinas/efectos adversos , Humanos , Ratones , Seguridad del Paciente , Serina Endopeptidasas/efectos de los fármacos , Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/efectos adversos
2.
European J Org Chem ; 2017(34): 5015-5024, 2017 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-28983191

RESUMEN

Cyclopropanes provide important design elements in medicinal chemistry and are widely present in drug compounds. Here we describe a strategy and extensive synthetic studies for the preparation of a diverse collection of cyclopropane-containing lead-like compounds, fragments and building blocks exploiting a single precursor. The bifunctional cyclopropane (E/Z)-ethyl 2-(phenylsulfanyl)-cyclopropane-1-carboxylate was designed to allow derivatization through the ester and sulfide functionalities to topologically varied compounds designed to fit in desirable chemical space for drug discovery. A cobalt-catalyzed cyclopropanation of phenyl vinyl sulfide affords these scaffolds on multigram scale. Divergent, orthogonal derivatization is achieved through hydrolysis, reduction, amidation and oxidation reactions as well as sulfoxide-magnesium exchange/functionalization. The cyclopropyl Grignard reagent formed from sulfoxide exchange is stable at 0 °C for > 2 h, which enables trapping with various electrophiles and Pd-catalyzed Negishi cross-coupling reactions. The library prepared, as well as a further virtual elaboration, is analyzed against parameters of lipophilicity (ALog P), MW and molecular shape by using the LLAMA (Lead-Likeness and Molecular Analysis) software, to illustrate the success in generating lead-like compounds and fragments.

3.
J Org Chem ; 75(21): 7475-8, 2010 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-20929205

RESUMEN

The low-temperature Evans-Tishchenko coupling of a range of functionalized heteroaryl aldehydes with ß-hydroxy ketones in the presence of a Sm(III) catalyst has been achieved with high yields (90-99%) and good to excellent diastereoselectivity (90:10 → 95:5 dr). However, at room temperature a retro-aldol aldol-Tishchenko reaction was found to compete with the desired Evans-Tishchenko reaction. Identification of these byproducts has allowed the corresponding aldol-Tishchenko reaction to be optimized for several heteroaryl aldehydes.


Asunto(s)
Aldehídos/química , Catálisis , Oxazoles/química , Samario/química , Temperatura
4.
Bioorg Med Chem Lett ; 16(7): 2022-5, 2006 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-16413778

RESUMEN

A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone (11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound (16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented.


Asunto(s)
Alcoholes/química , Morfolinas/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Cristalografía por Rayos X , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Morfolinas/química
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