Structure鈥揂ctivity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines

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• 作者：Diego Gonz脿lez Cabrera ; Frederic Douelle ; Claire Le Manach ; Ze Han ; Tanya Paquet ; Dale Taylor ; Mathew Njoroge ; Nina Lawrence ; Lubbe Wiesner ; David Waterson ; Michael J. Witty ; Sergio Wittlin ; Leslie J. Street ; Kelly Chibale
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7572-7579
• 全文大小：421K
• ISSN：1520-4804

文摘

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.