Plotkin Michael A, Labroli Marc, Schubert Jeffrey, Shaw Anthony, Schlegel Kelly-Ann S, Berger Richard, Cooke Andrew J, Hayes Robert P, Armacost Kira A, Kinek Keith, Krosky Paula, Burlein Christine, Meng Shi, DiNunzio Edward, Murray Edward M, Agrawal Sony, Madeira Maria, Flattery Amy, Yao Huifang, Leithead Andrew, Rose William A, Cox Christopher, Tellers David M, McKenna Philip M, Raheem Izzat
Discovery Chemistry, Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
Medicinal Chemistry, Exscientia, 53 State Street, Boston, Massachusetts 02109, United States.
ACS Med Chem Lett. 2024 Jul 9;15(8):1232-1241. doi: 10.1021/acsmedchemlett.4c00117. eCollection 2024 Aug 8.
Herpesvirus infections are ubiquitous, with over 95% of the adult population infected by at least one strain. While most of these infections resolve without treatment in healthy individuals, they can cause significant morbidity and mortality in immunocompromised, stem cell, or organ transplant patients. Current nucleoside standards of care provide meaningful benefit but are limited due to poor tolerability, resistance, and generally narrow spectrum of activity. Herpesviruses share a conserved DNA polymerase, the inhibition of which is validated as an effective strategy to disrupt viral replication. By utilizing a non-nucleoside inhibitor of the viral DNA polymerase, we sought to develop agents covering multiple herpesviruses (e.g., CMV, VZV, HSV1/2, EBV, and HHV6). Herein is described the invention of an oxazolidinone class of broad-spectrum non-nucleoside herpes antiviral inhibitors. A lead compound () with potent biochemical and broad-spectrum cellular activity was found to be efficacious in murine models against both HSV-1 and CMV infection.
疱疹病毒感染普遍存在，超过95%的成年人口感染过至少一种毒株。虽然这些感染在健康个体中大多无需治疗即可痊愈，但在免疫功能低下、干细胞或器官移植患者中，它们可导致严重的发病和死亡。目前的核苷类标准治疗方法有显著益处，但由于耐受性差、耐药性以及活性谱普遍较窄而受到限制。疱疹病毒共享一种保守的DNA聚合酶，抑制该酶被证实是破坏病毒复制的有效策略。通过使用病毒DNA聚合酶的非核苷抑制剂，我们试图开发覆盖多种疱疹病毒（如巨细胞病毒、水痘带状疱疹病毒、单纯疱疹病毒1/2型、EB病毒和人类疱疹病毒6型）的药物。本文描述了一类恶唑烷酮类广谱非核苷疱疹抗病毒抑制剂的发明。发现一种具有强大生化活性和广谱细胞活性的先导化合物（）在小鼠模型中对单纯疱疹病毒1型和巨细胞病毒感染均有效。
