Title
Selection of a respiratory syncytial virus fusion inhibitor clinical candidate, part 1: improving the pharmacokinetic profile using the structure-property relationship Selection of a respiratory syncytial virus fusion inhibitor clinical candidate, part 1: improving the pharmacokinetic profile using the structure-property relationship
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Washington, D.C. ,
Subject
Pharmacology. Therapy
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Volume/pages
50(2007) :19 , p. 4572-4584
ISSN
0022-2623
ISI
000249501500003
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
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