Novel multitarget-directed ligands aiming at symptoms and causes of Alzheimer's disease

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60162694%3AG44__%2F18%3A43889536" target="_blank" >RIV/60162694:G44__/18:43889536 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00179906:_____/18:10375712

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acschemneuro.8b00024" target="_blank" >https://pubs.acs.org/doi/10.1021/acschemneuro.8b00024</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acschemneuro.8b00024" target="_blank" >10.1021/acschemneuro.8b00024</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel multitarget-directed ligands aiming at symptoms and causes of Alzheimer's disease

Popis výsledku v původním jazyce

Alzheimer&apos;s disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT(6 )receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT(6 )receptors (K-i= 18 nM) and noncompetitive inhibitor of cholinesterases (IC50hAChE = 14 nM, IC50eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta antiaggregation activity (IC50 = 1.27 mu M) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.

Název v anglickém jazyce

Novel multitarget-directed ligands aiming at symptoms and causes of Alzheimer's disease

Popis výsledku anglicky

Alzheimer&apos;s disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT(6 )receptors, acetyl/butyrylcholinesterase inhibition, and amyloid beta antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT(6 )receptors (K-i= 18 nM) and noncompetitive inhibitor of cholinesterases (IC50hAChE = 14 nM, IC50eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid beta antiaggregation activity (IC50 = 1.27 mu M) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

—

Návaznosti

N - Vyzkumna aktivita podporovana z neverejnych zdroju

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ACS Chemical Neuroscience

ISSN

1948-7193

e-ISSN

—

Svazek periodika

9

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

20

Strana od-do

1195-1214

Kód UT WoS článku

000432752400031

EID výsledku v databázi Scopus

2-s2.0-85047154588