The human rhinovirus (hRV) is the causative agent of the common cold that often aggravates respiratory complications in patients with asthma or chronic obstructive pulmonary disease. The high rate of mutations and variety of serotypes are limiting the development of anti-hRV drugs, which emphasizes the need for the discovery of novel lead compounds. Previously, we identified antiviral compound 1 that we used here as the starting material for developing a novel compound series with high efficacy against hRV-A and -B. Improved metabolic stability was achieved by substituting an ester moiety with a 1,2,4-oxadiazole group. Specifically, compound 3k exhibited a high efficacy against hRV-B14, hRV-A21, and hRV-A71, with EC₅₀ values of 66.0, 22.0, and 3.7 nM, respectively, and a relevant hepatic stability (59.6 and 40.7% compound remaining after 30 min in rat and human liver microsomes, respectively). An in vivo study demonstrated that 3k possessed a desirable pharmacokinetic profile with low systemic clearance (0.158 L·h^–1·kg^–1) and modest oral bioavailability (27.8%). Hence, 3k appears to be an interesting candidate for the development of antiviral lead compounds.

中文翻译：

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具有抗人鼻病毒活性的3-芳基1,2,4-恶二唑衍生物

人鼻病毒（hRV）是普通感冒的病因，通常会加重哮喘或慢性阻塞性肺疾病患者的呼吸系统并发症。高突变率和血清型变化限制了抗hRV药物的开发，这强调了发现新型先导化合物的必要性。以前，我们鉴定了抗病毒化合物1，我们在这里将其用作开发对hRV-A和-B具有高功效的新型化合物系列的起始材料。通过用1,2,4-恶二唑基团取代酯部分，可以提高代谢稳定性。具体而言，化合物3K表现出对HRV-B14，HRV-A21，和HRV-A71高功效，用EC ₅₀分别为66.0、22.0和3.7 nM的值，以及相关的肝稳定性（大鼠和人肝微粒体30分钟后分别保留59.6和40.7％的化合物）。的体内研究表明，3K所具有的期望的药代动力学曲线具有低全身清除率（0.158 L·ħ ^-1 ·千克^-1）和适度的口服生物利用度（27.8％）。因此，3k似乎是抗病毒铅化合物开发的有趣候选者。