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Structure-Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines.
Gonzàlez Cabrera, Diego; Douelle, Frederic; Le Manach, Claire; Han, Ze; Paquet, Tanya; Taylor, Dale; Njoroge, Mathew; Lawrence, Nina; Wiesner, Lubbe; Waterson, David; Witty, Michael J; Wittlin, Sergio; Street, Leslie J; Chibale, Kelly.
Afiliação
  • Gonzàlez Cabrera D; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
  • Douelle F; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
  • Le Manach C; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
  • Han Z; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
  • Paquet T; Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
  • Taylor D; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town 7925, South Africa.
  • Njoroge M; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town 7925, South Africa.
  • Lawrence N; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town 7925, South Africa.
  • Wiesner L; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town 7925, South Africa.
  • Waterson D; Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
  • Witty MJ; Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
  • Wittlin S; Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
  • Street LJ; Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
  • Chibale K; University of Basel , 4002 Basel, Switzerland.
J Med Chem ; 58(18): 7572-9, 2015 Sep 24.
Article em En | MEDLINE | ID: mdl-26322748
ABSTRACT
Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Antimaláricos Limite: Animals / Female / Humans / Male Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: África do Sul
Texto completo
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Antimaláricos Limite: Animals / Female / Humans / Male Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: África do Sul