Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA.
J Med Chem. 2012 Apr 12;55(7):3535-45. doi: 10.1021/jm300214e. Epub 2012 Apr 3.
Arboviral encephalitis is a potentially devastating human disease with no approved therapies that target virus replication. We previously discovered a novel class of thieno[3,2-b]pyrrole-based inhibitors active against neurotropic alphaviruses such as western equine encephalitis virus (WEEV) in cultured cells. In this report, we describe initial development of these novel antiviral compounds, including bioisosteric replacement of the 4H-thieno[3,2-b]pyrrole core with indole to improve metabolic stability and the introduction of chirality to assess target enantioselectivity. Selected modifications enhanced antiviral activity while maintaining low cytotoxicity, increased stability to microsomal metabolism, and also revealed striking enantiospecific activity in cultured cells. Furthermore, we demonstrate improved outcomes (both symptoms and survival) following treatment with indole analogue 9h (CCG-203926) in an in vivo mouse model of alphaviral encephalitis that closely correlate with the enantiospecific in vitro antiviral activity. These results represent a substantial advancement in the early preclinical development of a promising class of novel antiviral drugs against virulent neurotropic alphaviruses.
虫媒脑炎是一种具有潜在破坏性的人类疾病，目前尚无针对病毒复制的批准疗法。我们之前发现了一类新型噻吩并[3,2-b]吡咯类抑制剂，它们在培养的细胞中对亲神经的甲病毒（如西方马脑炎病毒（WEEV））具有活性。在本报告中，我们描述了这些新型抗病毒化合物的初步开发情况，包括用吲哚替代 4H-噻吩并[3,2-b]吡咯核心以提高代谢稳定性，以及引入手性以评估靶标对映选择性。选定的修饰提高了抗病毒活性，同时保持低细胞毒性，增加了对微粒体代谢的稳定性，并且在培养的细胞中还显示出惊人的对映体特异性活性。此外，我们在亲神经甲病毒脑炎的体内小鼠模型中证明了吲哚类似物 9h（CCG-203926）治疗后的改善结果（症状和存活率），这与体外对映选择性抗病毒活性密切相关。这些结果代表了针对毒力亲神经甲病毒的一类新型有希望的抗病毒药物的早期临床前开发的重大进展。
