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

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

  • Eur J Med Chem. 2024 Oct 5:276:116690. doi: 10.1016/j.ejmech.2024.116690.
Prashant Chakrasali 1,  Dasom Hwang 2,  Joo-Youn Lee 2,  Eunhye Jung 2,  Hye Lim Lee 2,  Alba Reneesh 1,  Adam Skarka 3,  Kamil Musilek 3,  Nhung Hong Nguyen 4,  Jin Soo Shin 5,  Young-Sik Jung 6
Affiliations

Affiliations

  • 1 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.
  • 2 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 3 Department of Chemistry, Faculty of Science, University of Hradec Kralove, Czech Republic.
  • 4 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.
  • 5 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea. Electronic address: jsshin@krict.re.kr.
  • 6 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.
PMID: 39032404 DOI: 10.1016/j.ejmech.2024.116690
Abstract

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.

Keywords

Antiviral compound; Enterovirus; Human rhinovirus; PI4KIIIβ; Pyrazolo-pyrimidine.

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