Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121)

Autor:	Philippe Muller, Pieter Van Remoortere, Rudy Edmond Willebrords, Fortin Jerome Michel Claude, Tom Valerius Josepha Gevers, Koen Andries, Christophe Meyer, Piet Wigerinck, Heidi Szel, Jean-François Bonfanti, Janssens Frans Eduard, Philip Timmerman, Frederic Marc Maurice Doublet, Peggy Janssens, Koen Wuyts, Laurence Queguiner
Rok vydání:	2008
Předmět:	Male Models Molecular Paramyxoviridae Pyridines Morpholines Fusion inhibitor Computational biology Antiviral Agents Virus Rats Sprague-Dawley Structure-Activity Relationship Drug Discovery Drug Resistance Viral Structure–activity relationship Animals Sigmodontinae Mononegavirales Binding Sites biology Chemistry Pharmacology. Therapy Virus Internalization biology.organism_classification Rats Respiratory Syncytial Viruses Sprague dawley Biochemistry Mutation Molecular Medicine Benzimidazoles Viral Fusion Proteins Protein Binding
Zdroj:	Journal of medicinal chemistry
ISSN:	0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8bccd604791964784d9bd96c5c4ca306 https://pubmed.ncbi.nlm.nih.gov/18254606 Zobrazit plný text záznamu