Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121)

被引：82

作者：

Bonfanti, Jean-Francois ^{[1
]}

Meyer, Christophe ^{[1
]}

Doublet, Frederic ^{[1
]}

Fortin, Jerome ^{[1
]}

Muller, Philippe ^{[1
]}

Queguiner, Laurence ^{[1
]}

Gevers, Tom ^{[2
]}

Janssens, Peggy ^{[2
]}

Szel, Heidi ^{[2
]}

Willebrords, Rudy ^{[2
]}

Timmerman, Philip ^{[3
]}

Wuyts, Koen ^{[3
]}

van Remoortere, Pieter ^{[5
]}

Janssens, Frans ^{[4
]}

Wigerinck, Piet ^{[5
]}

Andries, Koen ^{[2
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev, Med Chem Dept, F-27106 Val de Reuil, France

[2] Johnson & Johnson Pharmaceut Res & Dev, Antimicrobial Res Dept, B-2340 Beerse, Belgium

[3] Johnson & Johnson Pharmaceut Res & Dev, ADME Tox & Bioanal Dept, B-2340 Beerse, Belgium

[4] Johnson & Johnson Pharmaceut Res & Dev, Dept Med Chem, B-2340 Beerse, Belgium

[5] Tibotec BVBA, B-2800 Mechelen, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 04期

关键词：

D O I：

10.1021/jm701284j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：875 / 896

页数：22

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