2008 · JOURNAL OF MEDICINAL CHEMISTRY

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

Bonfanti, Jean-Francois, Meyer, Christophe, Doublet, Frederic, Fortin, Jerome, Muller, Philippe, Queguiner, Laurence, Gevers, Tom, Janssens, Peggy, Szel, Heidi, Willebrords, Rudy, Timmerman, Philip, Wuyts, Koen, van Remoortere, Pieter, Janssens, Frans, Wigerinck, Piet, Andries, Koen

Journal: JOURNAL OF MEDICINAL CHEMISTRY
Année: 2008
Volume: 51
Numéro: 4
Pages: 875-896
Mois: FEB 28
DOI: 10.1021/jm701284j

Abstract

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.

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