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.
Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
Eur J Med Chem. 2024 Oct 5;276:116690. doi: 10.1016/j.ejmech.2024.116690. Epub 2024 Jul 17.
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 (EC = 0.044, 0.066, and 0.083 μM for hRV-B14, hRV-A16, and hRV-A21, respectively) and moderate toxicity (CC = 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 (IC 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 kg) and modest oral bioavailability (52.4 %). Hence, 6f (KR-26549) appears to be an ideal lead for the development of new antiviral drugs.
通过靶向病毒复制蛋白来展示广谱肠病毒抑制活性的小分子在抗病毒药物研发中备受关注。为了发现新的人鼻病毒（hRV）抑制剂，我们对韩国化学银行库中的 10 万个化合物进行了高通量筛选。这次搜索发现了两种具有吡唑并嘧啶核心结构的磷脂酰肌醇-4-激酶 IIIβ（PI4KIIIβ）抑制剂，它们具有中等的抗鼻病毒活性和轻微的细胞毒性。旨在优化命中化合物活性的研究结果表明，吡唑并嘧啶衍生物 6f 表现出最高的活性（对 hRV-B14、hRV-A16 和 hRV-A21 的 EC 值分别为 0.044、0.066 和 0.083 μM）和适度的毒性（CC = 31.38 μM）。此外，6f 对各种 hRV、柯萨奇病毒和其他肠道病毒，如 EV-A71、EV-D68 具有广谱活性。激酶抑制活性评估表明，6f 对 PI4KIIIβ 具有高选择性抑制活性（IC 值为 0.057 μM），而对 PI4KIIIα 则无抑制活性（>10 μM）。此外，6f 在肝脏中的稳定性适中（在小鼠和人肝微粒体中分别 30 分钟后分别剩余 46.9%和 55.3%）。最后，体内研究表明，6f 具有理想的药代动力学特征，表现为低全身清除率（0.48 L∙h kg）和适度的口服生物利用度（52.4%）。因此，6f（KR-26549）似乎是开发新型抗病毒药物的理想先导化合物。
