title: Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121).
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.
authors.affiliation: Medicinal Chemistry Department, Johnson & Johnson Pharmaceutical Research and Development, Campus de Maigremont, BP 615, F-27106 Val de Reuil, France. jbonfant@prdfr.jnj.com
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bonfanti
authors.forename: Christophe
authors.initials: C
authors.lastname: Meyer
authors.forename: Frédéric
authors.initials: F
authors.lastname: Doublet
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fortin
authors.forename: Philippe
authors.initials: P
authors.lastname: Muller
authors.forename: Laurence
authors.initials: L
authors.lastname: Queguiner
authors.forename: Tom
authors.initials: T
authors.lastname: Gevers
authors.forename: Peggy
authors.initials: P
authors.lastname: Janssens
authors.forename: Heidi
authors.initials: H
authors.lastname: Szel
authors.forename: Rudy
authors.initials: R
authors.lastname: Willebrords
authors.forename: Philip
authors.initials: P
authors.lastname: Timmerman
authors.forename: Koen
authors.initials: K
authors.lastname: Wuyts
authors.forename: Pieter
authors.initials: P
authors.lastname: van Remoortere
authors.forename: Frans
authors.initials: F
authors.lastname: Janssens
authors.forename: Piet
authors.initials: P
authors.lastname: Wigerinck
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D024882:Drug Resistance, Viral; D008297:Male; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009154:Mutation; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012136:Respiratory Syncytial Viruses / Q000187:drug effects* / Q000502:physiology; D016205:Sigmodontinae; D013329:Structure-Activity Relationship; D014760:Viral Fusion Proteins / Q000235:genetics*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: C528854:2-(6-((2-(3-hydroxypropyl)-5-methylphenylamino)methyl)-2-(3-morpholin-4-ylpropylamino)benzoimidazol-1-ylmethyl)-6-methylpyridin-3-ol; D000998:Antiviral Agents; D001562:Benzimidazoles; D009025:Morpholines; D011725:Pyridines; D014760:Viral Fusion Proteins