7-Amino-3-phenyl-2-methyl-pyrazolopyrimidine derivatives inhibit human rhinovirus replication
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
7-Amino-3-phenyl-2-methyl-pyrazolopyrimidine derivatives inhibit human rhinovirus replication
Original language description
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 <bold>6f</bold> 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, <bold>6f</bold> 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 <bold>6f</bold> possesses a high and selective kinase inhibition activity against PI4KIII beta (IC50 value of 0.057 mu M) and not against PI4KIII alpha (>10 mu M). Moreover, <bold>6f</bold> 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 <bold>6f</bold> 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, <bold>6f</bold> (KR-26549) appears to be an ideal lead for the development of new antiviral drugs.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30107 - Medicinal chemistry
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
European Journal of Medicinal Chemistry
ISSN
0223-5234
e-ISSN
1768-3254
Volume of the periodical
276
Issue of the periodical within the volume
October
Country of publishing house
FR - FRANCE
Number of pages
11
Pages from-to
"Article Number: 116690"
UT code for WoS article
001276864000001
EID of the result in the Scopus database
2-s2.0-85199095459