Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate. 2. Discovery of a Morpholinopropylaminobenzimidazole Derivative (TMC353121)
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- 作者：Jean-Franç ; ois Bonfanti ; Christophe Meyer ; Fré ; dé ; ric Doublet ; Jé ; rô ; me Fortin ; Philippe Muller ; Laurence Queguiner ; Tom Gevers ; Peggy Janssens ; Heidi Szel ; Rudy Willebrords ; Phili
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：February 28, 2008
- 年：2008
- 卷：51
- 期：4
- 页码：875 - 896
- 全文大小：1174K
- 年卷期：v.51,no.4(February 28, 2008)
- ISSN：1520-4804
文摘
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.