Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121).
Bonfanti JF,
Meyer C,
Doublet F,
Fortin J,
Muller P,
Queguiner L,
Gevers T,
Janssens P,
Szel H,
Willebrords R,
Timmerman P,
Wuyts K,
van Remoortere P,
Janssens F,
Wigerinck P,
Andries K.
Medicinal Chemistry Department, Johnson & Johnson Pharmaceutical Research and Development, Campus de Maigremont, BP 615, F-27106 Val de Reuil, France. jbonfant@prdfr.jnj.com
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.
PMID: 18254606 [PubMed - indexed for MEDLINE]