Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121).
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.
Bonfanti
Jean-François
JF
Medicinal Chemistry Department, Johnson & Johnson Pharmaceutical Research and Development, Campus de Maigremont, BP 615, F-27106 Val de Reuil, France. jbonfant@prdfr.jnj.com
Meyer
Christophe
C
Doublet
Frédéric
F
Fortin
Jérôme
J
Muller
Philippe
P
Queguiner
Laurence
L
Gevers
Tom
T
Janssens
Peggy
P
Szel
Heidi
H
Willebrords
Rudy
R
Timmerman
Philip
P
Wuyts
Koen
K
van Remoortere
Pieter
P
Janssens
Frans
F
Wigerinck
Piet
P
Andries
Koen
K
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*
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