化学
铅化合物
效力
药物发现
单反病毒
药理学
咪唑吡啶
口服活性
药代动力学
病毒
结构-活动关系
副粘病毒科
病毒学
组合化学
体外
生物化学
病毒性疾病
医学
作者
Song Feng,Chao Li,Dongdong Chen,Xiufang Zheng,Yun Hua,Lu Gao,Hong C. Shen
标识
DOI:10.1016/j.ejmech.2017.07.032
摘要
Recently we described a novel class of imidazopyridine compounds that showed exceptional anti-RSV potency in cell culture. However, unfavorable pharmacokinetic (PK) properties and glutathione (GSH) adduct liabilities impeded their further development. In a bid to address the PK and early safety concerns, a small compound library consisting of dozens of scaffold-hopping analogues was designed and synthesized for RSV CPE assay screening, which led to the identification of a new chemical starting point: methylsulfonyl indole compound 8. In this paper, we report the discovery and optimization of a series of methylsulfonyl indazoles as potent RSV fusion inhibitors. In particular, compound 47 was orally efficacious in a RSV mouse model, with 1.6 log unit viral load reduction at 25 mg/kg BID upon oral dosing. The results may have broad implications for the design of new RSV fusion inhibitors, and demonstrate the potential for developing novel therapies for RSV infection.
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