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

P. Chakrasali, D. Hwang, JY. Lee, E. Jung, HL. Lee, A. Reneesh, A. Skarka, K. Musilek, NH. Nguyen, JS. Shin, YS. Jung

. 2024 ; 276 (-) : 116690. [pub] 20240717

Language English Country France

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24018723

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 IIIβ (PI4KIIIβ) 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 6f exhibits the highest activity (EC50 = 0.044, 0.066, and 0.083 μM for hRV-B14, hRV-A16, and hRV-A21, respectively) and moderate toxicity (CC50 = 31.38 μM). Furthermore, 6f 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 6f possesses a high and selective kinase inhibition activity against PI4KIIIβ (IC50 value of 0.057 μM) and not against PI4KIIIα (>10 μM). Moreover, 6f 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 6f possesses a desirable pharmacokinetic profile reflected in low systemic clearance (0.48 L∙h-1 kg-1) and modest oral bioavailability (52.4 %). Hence, 6f (KR-26549) appears to be an ideal lead for the development of new antiviral drugs.

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$a 7-Amino-3-phenyl-2-methyl-pyrazolopyrimidine derivatives inhibit human rhinovirus replication / $c P. Chakrasali, D. Hwang, JY. Lee, E. Jung, HL. Lee, A. Reneesh, A. Skarka, K. Musilek, NH. Nguyen, JS. Shin, YS. Jung
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$a 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 IIIβ (PI4KIIIβ) 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 6f exhibits the highest activity (EC50 = 0.044, 0.066, and 0.083 μM for hRV-B14, hRV-A16, and hRV-A21, respectively) and moderate toxicity (CC50 = 31.38 μM). Furthermore, 6f 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 6f possesses a high and selective kinase inhibition activity against PI4KIIIβ (IC50 value of 0.057 μM) and not against PI4KIIIα (>10 μM). Moreover, 6f 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 6f possesses a desirable pharmacokinetic profile reflected in low systemic clearance (0.48 L∙h-1 kg-1) and modest oral bioavailability (52.4 %). Hence, 6f (KR-26549) appears to be an ideal lead for the development of new antiviral drugs.
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$a Hwang, Dasom $u Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea
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$a Lee, Joo-Youn $u Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea
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$a Jung, Eunhye $u Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea
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$a Lee, Hye Lim $u Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea
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$a Reneesh, Alba $u Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, 34113, Republic of Korea
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$a Skarka, Adam $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Czech Republic
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$a Musilek, Kamil $u Department of Chemistry, Faculty of Science, University of Hradec Kralove, Czech Republic
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$a Nguyen, Nhung Hong $u Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon, 34113, Republic of Korea; Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea
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$a Shin, Jin Soo $u Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea. Electronic address: jsshin@krict.re.kr
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$a Jung, Young-Sik $u Infectious 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. Electronic address: ysjung@krict.re.kr
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