7-Amino-3-phenyl-2-methyl-pyrazolopyrimidine derivatives inhibit human rhinovirus replication
Prashant Chakrasali1, Dasom Hwang2, Joo-Youn Lee2
1Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, 34113, Republic of Korea.
European Journal of Medicinal Chemistry
|July 20, 2024
Summary
Researchers discovered a new pyrazolo-pyrimidine derivative, 6f, that shows broad-spectrum enteroviral inhibitory activity. This compound targets PI4KIIIβ and demonstrates promising potential as a lead for developing novel antiviral drugs against various enteroviruses.
Area of Science:
- Medicinal Chemistry
- Virology
- Drug Discovery
Background:
- Small molecules targeting viral replication proteins are crucial for antiviral drug discovery.
- Enteroviral infections pose a significant public health challenge, necessitating new therapeutic strategies.
- Human rhinovirus (hRV) and other enteroviruses are significant pathogens.
Purpose of the Study:
- To identify novel inhibitors of human rhinovirus (hRV) replication.
- To discover small molecules with broad-spectrum enteroviral inhibitory activity.
- To optimize lead compounds for enhanced antiviral efficacy and favorable pharmacokinetic properties.
Main Methods:
- High-throughput screening of 100,000 compounds from the Korea Chemical Bank library.
- Identification and characterization of phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) inhibitors.
- In vitro antiviral activity assays (EC50), cytotoxicity assays (CC50), kinase inhibition assays (IC50), liver microsome stability assays, and in vivo pharmacokinetic studies.
Main Results:
- Two pyrazolo-pyrimidine derivatives were identified as PI4KIIIβ inhibitors with moderate anti-rhinoviral activity.
- Derivative 6f exhibited potent activity against hRV-B14, hRV-A16, and hRV-A21 (EC50 = 0.044–0.083 μM) with moderate toxicity (CC50 = 31.38 μM).
- Compound 6f demonstrated broad-spectrum activity against various enteroviruses, including EV-A71 and EV-D68, with selective PI4KIIIβ inhibition and favorable in vivo pharmacokinetics.
Conclusions:
- The pyrazolo-pyrimidine derivative 6f is a potent and selective PI4KIIIβ inhibitor with broad-spectrum enteroviral activity.
- Compound 6f exhibits promising antiviral efficacy, moderate toxicity, and a desirable pharmacokinetic profile.
- 6f (KR-26549) represents an ideal lead compound for the development of new antiviral therapeutics against enteroviral infections.
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