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

  • J Med Chem. 2008 Feb 28;51(4):875-96. doi: 10.1021/jm701284j.
Jean-François Bonfanti  1 ,  Christophe Meyer ,  Frédéric Doublet ,  Jérôme Fortin ,  Philippe Muller ,  Laurence Queguiner ,  Tom Gevers ,  Peggy Janssens ,  Heidi Szel ,  Rudy Willebrords ,  Philip Timmerman ,  Koen Wuyts ,  Pieter van Remoortere ,  Frans Janssens ,  Piet Wigerinck ,  Koen Andries
Affiliations
  • 1. Medicinal Chemistry Department, Johnson & Johnson Pharmaceutical Research and Development, Campus de Maigremont, BP 615, F-27106 Val de Reuil, France. [email protected]
PMID: 18254606 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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