Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121)
Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121)
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DOI：
10.1021/jm701284j
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发表时间：
2008-02-28
影响因子：
7.3
通讯作者：
Andries, Koen
中科院分区：
文献类型：
--
作者：
Bonfanti, Jean-Francois;Meyer, Christophe;Andries, Koen
先前的论文（Bonfanti等人，J. Med Chem.2007，50，4572-4584）报道了通过减少取代的苯并咪唑的组织保留来优化其药代动力学特征。然而，实现这一目标所必需的修饰也导致抗RSV活性的显著下降。本文描述了一项分子建模研究，随后进行了一项先导优化程序，该程序恢复了最初的强效抗病毒活性，并选择TMC 353121作为临床候选药物。
A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.