Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate. 2. Discovery of a Morpholinopropylaminobenzimidazole Derivative (TMC353121).
Journal of medicinal chemistry 2008 Feb 7; In press
Bonfanti J 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, B.P. 615, F-27106 Val de Reuil, France, Antimicrobial Research Department, ADME-Tox & Bioanalysis Department, and Medicinal Chemistry
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.
Keywords: Respiratory Syncytial Virus TMC353121