Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate. 2. Discovery of a Morpholinopropylaminobenzimidazole Derivative (TMC353121)

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

doi:10.1021/jm701284j.s001

jm701284j_si_001.pdf (49.53 kB)

Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate. 2. Discovery of a Morpholinopropylaminobenzimidazole Derivative (TMC353121)

journal contribution

posted on 2008-02-28, 00:00 authored by Jean-François Bonfanti, 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

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.