7-Amino-3-phenyl-2-methyl-pyrazolopyrimidine derivatives inhibit human rhinovirus replication

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F24%3A50021625" target="_blank" >RIV/62690094:18470/24:50021625 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0223523424005701?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523424005701?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2024.116690" target="_blank" >10.1016/j.ejmech.2024.116690</a>

Jazyk výsledku

angličtina

Název v původním jazyce

7-Amino-3-phenyl-2-methyl-pyrazolopyrimidine derivatives inhibit human rhinovirus replication

Popis výsledku v původním jazyce

Small molecules that exhibit broad-spectrum enteroviral inhibitory activity by targeting viral replication proteins are highly desired in antiviral drug discovery studies. To discover new human rhinovirus (hRV) inhibitors, we performed a high-throughput screening of 100,000 compounds from the Korea Chemical Bank library. This search led to identification of two phosphatidylinositol-4-kinase III beta (PI4KIII beta) inhibitors having the pyrazolo-pyrimidine core structure, which display moderate anti-rhinoviral activity along with mild cytotoxicity. The results of a study aimed at optimizing the activity of the hit compounds showed that the pyrazolo-pyrimidine derivative &lt;bold&gt;6f&lt;/bold&gt; exhibits the highest activity (EC50 = 0.044, 0.066, and 0.083 mu M for hRV-B14, hRV-A16, and hRV-A21, respectively) and moderate toxicity (CC50 = 31.38 mu M). Furthermore, &lt;bold&gt;6f&lt;/bold&gt; has broad-spectrum activities against various hRVs, coxsackieviruses and other enteroviruses, such as EV-A71, EV-D68. An assessment of kinase inhibition potencies demonstrated that &lt;bold&gt;6f&lt;/bold&gt; possesses a high and selective kinase inhibition activity against PI4KIII beta (IC50 value of 0.057 mu M) and not against PI4KIII alpha (&gt;10 mu M). Moreover, &lt;bold&gt;6f&lt;/bold&gt; exhibits modest hepatic stability (46.9 and 55.3 % remaining after 30 min in mouse and human liver microsomes, respectively). Finally, an in vivo study demonstrated that &lt;bold&gt;6f&lt;/bold&gt; possesses a desirable pharmacokinetic profile reflected in low systemic clearance (0.48 L center dot h(-1) kg(-1)) and modest oral bioavailability (52.4 %). Hence, &lt;bold&gt;6f&lt;/bold&gt; (KR-26549) appears to be an ideal lead for the development of new antiviral drugs.

Název v anglickém jazyce

7-Amino-3-phenyl-2-methyl-pyrazolopyrimidine derivatives inhibit human rhinovirus replication

Popis výsledku anglicky

Small molecules that exhibit broad-spectrum enteroviral inhibitory activity by targeting viral replication proteins are highly desired in antiviral drug discovery studies. To discover new human rhinovirus (hRV) inhibitors, we performed a high-throughput screening of 100,000 compounds from the Korea Chemical Bank library. This search led to identification of two phosphatidylinositol-4-kinase III beta (PI4KIII beta) inhibitors having the pyrazolo-pyrimidine core structure, which display moderate anti-rhinoviral activity along with mild cytotoxicity. The results of a study aimed at optimizing the activity of the hit compounds showed that the pyrazolo-pyrimidine derivative &lt;bold&gt;6f&lt;/bold&gt; exhibits the highest activity (EC50 = 0.044, 0.066, and 0.083 mu M for hRV-B14, hRV-A16, and hRV-A21, respectively) and moderate toxicity (CC50 = 31.38 mu M). Furthermore, &lt;bold&gt;6f&lt;/bold&gt; has broad-spectrum activities against various hRVs, coxsackieviruses and other enteroviruses, such as EV-A71, EV-D68. An assessment of kinase inhibition potencies demonstrated that &lt;bold&gt;6f&lt;/bold&gt; possesses a high and selective kinase inhibition activity against PI4KIII beta (IC50 value of 0.057 mu M) and not against PI4KIII alpha (&gt;10 mu M). Moreover, &lt;bold&gt;6f&lt;/bold&gt; exhibits modest hepatic stability (46.9 and 55.3 % remaining after 30 min in mouse and human liver microsomes, respectively). Finally, an in vivo study demonstrated that &lt;bold&gt;6f&lt;/bold&gt; possesses a desirable pharmacokinetic profile reflected in low systemic clearance (0.48 L center dot h(-1) kg(-1)) and modest oral bioavailability (52.4 %). Hence, &lt;bold&gt;6f&lt;/bold&gt; (KR-26549) appears to be an ideal lead for the development of new antiviral drugs.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

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

276

Číslo periodika v rámci svazku

October

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

11

Strana od-do

"Article Number: 116690"

Kód UT WoS článku

001276864000001

EID výsledku v databázi Scopus

2-s2.0-85199095459