RESUMO
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.
Assuntos
Antivirais/síntese química , Benzimidazóis/síntese química , Morfolinas/síntese química , Piridinas/síntese química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Proteínas Virais de Fusão/genética , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Sítios de Ligação , Farmacorresistência Viral , Masculino , Modelos Moleculares , Morfolinas/farmacocinética , Morfolinas/farmacologia , Mutação , Ligação Proteica , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Vírus Sinciciais Respiratórios/fisiologia , Sigmodontinae , Relação Estrutura-AtividadeRESUMO
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.