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Design and synthesis of tetrahydropyridopyrimidine based Toll-Like Receptor (TLR) 7/8 dual agonists.
McGowan, David C; Herschke, Florence; Khamlichi, Mourad D; Rosauro, Mari Luz; Benedicto, Sara M Pérez; Pauwels, Frederik; Stoops, Bart; Pande, Vineet; Scholliers, Annick; Van Schoubroeck, Bertrand; Mostmans, Wendy; Van Dijck, Kris; Thoné, Tine; Horton, Helen; Fanning, Gregory; Jonckers, Tim H M; Raboisson, Pierre.
Affiliation
  • McGowan DC; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: dmcgowan@its.jnj.com.
  • Herschke F; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Khamlichi MD; Villapharma Research, Parque Tecnológico de Fuente Álamo, Ctra. El Estrecho-Lobosillo, Km. 2,5-Av. Azul, 30320 Fuente Álamo de Murcia, Murcia, Spain.
  • Rosauro ML; Villapharma Research, Parque Tecnológico de Fuente Álamo, Ctra. El Estrecho-Lobosillo, Km. 2,5-Av. Azul, 30320 Fuente Álamo de Murcia, Murcia, Spain.
  • Benedicto SMP; Villapharma Research, Parque Tecnológico de Fuente Álamo, Ctra. El Estrecho-Lobosillo, Km. 2,5-Av. Azul, 30320 Fuente Álamo de Murcia, Murcia, Spain.
  • Pauwels F; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Stoops B; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Pande V; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Scholliers A; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Van Schoubroeck B; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Mostmans W; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Van Dijck K; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Thoné T; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Horton H; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Fanning G; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Jonckers THM; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Raboisson P; Janssen Infectious Diseases, Turnhoutseweg 30, 2340 Beerse, Belgium.
Bioorg Med Chem Lett ; 28(19): 3216-3221, 2018 10 15.
Article in En | MEDLINE | ID: mdl-30143425
ABSTRACT
In a continuing effort to discover novel TLR agonists, herein we report on the discovery and structure-activity relationship of novel tetrahydropyridopyrimidine TLR 7/8 agonists. Optimization of this series towards dual agonist activity and a high clearance profile resulted in the identification of compound 52a1. Evaluation in vivo revealed an interferon stimulated response (ISG) in mice with limited systemic exposure and demonstrated the potential in antiviral treatment or as a vaccine adjuvant.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Toll-Like Receptor 7 / Toll-Like Receptor 8 Limits: Animals Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2018 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Toll-Like Receptor 7 / Toll-Like Receptor 8 Limits: Animals Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2018 Document type: Article