SC-560 and mofezolac isosteres as new potent COX-1 selective inhibitors with antiplatelet effect

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F23%3A00570616" target="_blank" >RIV/61389030:_____/23:00570616 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11160/23:10470932

Výsledek na webu

<a href="https://doi.org/10.1002/ardp.202200549" target="_blank" >https://doi.org/10.1002/ardp.202200549</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/ardp.202200549" target="_blank" >10.1002/ardp.202200549</a>

Jazyk výsledku

angličtina

Název v původním jazyce

SC-560 and mofezolac isosteres as new potent COX-1 selective inhibitors with antiplatelet effect

Popis výsledku v původním jazyce

Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC50 values in the nanomolar range (9–252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.

Název v anglickém jazyce

SC-560 and mofezolac isosteres as new potent COX-1 selective inhibitors with antiplatelet effect

Popis výsledku anglicky

Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC50 values in the nanomolar range (9–252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/LTC18065" target="_blank" >LTC18065: Selektivní COX-1 inhibice jako cardioprotektivní terapeutický záměr</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

Archiv der Pharmazie

ISSN

0365-6233

e-ISSN

1521-4184

Svazek periodika

356

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

12

Strana od-do

e2200549

Kód UT WoS článku

000932685300001

EID výsledku v databázi Scopus

2-s2.0-85147937585