title: Selection of a respiratory syncytial virus fusion inhibitor clinical candidate, part 1: improving the pharmacokinetic profile using the structure-property relationship.
abstract: We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry Department, Campus de Maigremont BP315, F-27106 Val de Reuil, France. jbonfant@prdfr.jnj.com
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bonfanti
authors.forename: Frédéric
authors.initials: F
authors.lastname: Doublet
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fortin
authors.forename: Jean
authors.initials: J
authors.lastname: Lacrampe
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guillemont
authors.forename: Philippe
authors.initials: P
authors.lastname: Muller
authors.forename: Laurence
authors.initials: L
authors.lastname: Queguiner
authors.forename: Eric
authors.initials: E
authors.lastname: Arnoult
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: Frans
authors.initials: F
authors.lastname: Janssens
authors.forename: Cois
authors.initials: C
authors.lastname: Sommen
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* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors*
chemical_list: C481509:2((2-((1-(2-aminoethyl)-4-piperidinyl)amino)-4-methyl-1H-benzimidazol-1-yl)methyl)-6-methyl-3-pyridinol; D000998:Antiviral Agents; D001562:Benzimidazoles; D010880:Piperidines; D011725:Pyridines; D014760:Viral Fusion Proteins