Development of submicromolar 17 beta-HSD10 inhibitors and their in vitro and in vivo evaluation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F23%3A10466920" target="_blank" >RIV/00179906:_____/23:10466920 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60162694:G44__/24:00560281 RIV/62690094:18470/23:50020605

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=b3n._oKRKk" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=b3n._oKRKk</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2023.115593" target="_blank" >10.1016/j.ejmech.2023.115593</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Development of submicromolar 17 beta-HSD10 inhibitors and their in vitro and in vivo evaluation

Popis výsledku v původním jazyce

17 beta-hydroxysteroid dehydrogenase type 10 (17 beta-HSD10) is a multifunctional mitochondrial enzyme and putative drug target for the treatment of various pathologies including Alzheimer&apos;s disease or some types of hormone-dependent cancer. In this study, a series of new benzothiazolylurea-based inhibitors were developed based on the structure-activity relationship (SAR) study of previously published compounds and predictions of their physicochemical properties. This led to the identification of several submicromolar inhibitors (IC50 similar to 0.3 mu M), the most potent compounds within the benzothiazolylurea class known to date. The positive interaction with 17 beta-HSD10 was further confirmed by differential scanning fluorimetry and the best molecules were found to be cell penetrable. In addition, the best compounds weren&apos;t found to have additional effects for mitochondrial off-targets and cytotoxic or neurotoxic effects. The two most potent inhibitors 9 and 11 were selected for in vivo pharmacokinetic study after intravenous and peroral administration. Although the pharmacokinetic results were not fully conclusive, it seemed that compound 9 was bioavailable after peroral administration and could penetrate into the brain (brain-plasma ratio 0.56).

Název v anglickém jazyce

Development of submicromolar 17 beta-HSD10 inhibitors and their in vitro and in vivo evaluation

Popis výsledku anglicky

17 beta-hydroxysteroid dehydrogenase type 10 (17 beta-HSD10) is a multifunctional mitochondrial enzyme and putative drug target for the treatment of various pathologies including Alzheimer&apos;s disease or some types of hormone-dependent cancer. In this study, a series of new benzothiazolylurea-based inhibitors were developed based on the structure-activity relationship (SAR) study of previously published compounds and predictions of their physicochemical properties. This led to the identification of several submicromolar inhibitors (IC50 similar to 0.3 mu M), the most potent compounds within the benzothiazolylurea class known to date. The positive interaction with 17 beta-HSD10 was further confirmed by differential scanning fluorimetry and the best molecules were found to be cell penetrable. In addition, the best compounds weren&apos;t found to have additional effects for mitochondrial off-targets and cytotoxic or neurotoxic effects. The two most potent inhibitors 9 and 11 were selected for in vivo pharmacokinetic study after intravenous and peroral administration. Although the pharmacokinetic results were not fully conclusive, it seemed that compound 9 was bioavailable after peroral administration and could penetrate into the brain (brain-plasma ratio 0.56).

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/EF18_069%2F0010054" target="_blank" >EF18_069/0010054: IT4Neuro(degeneration)</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Svazek periodika

258

Číslo periodika v rámci svazku

October

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

18

Strana od-do

115593

Kód UT WoS článku

001030059600001

EID výsledku v databázi Scopus

2-s2.0-85163144943