Novel Orally Active Antimalarial Thiazoles

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• 作者：Diego Gonz谩lez Cabrera ; Frederic Douelle ; Tzu-Shean Feng ; Aloysius T. Nchinda ; Yassir Younis ; Karen L. White ; Quoc Wu ; Eileen Ryan ; Jeremy N. Burrows ; David Waterson ; Michael J. Witty ; Sergio Wittlin ; Susan A. Charman ; Kelly Chibale
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7713-7719
• 全文大小：851K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC₅₀: 0.08 渭M (K1, chloroquine and multidrug resistant strain) and 0.07 渭M (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Compound 3 also exhibited in vivo activity in the P. berghei mouse model at 4 脳 50 mg/kg administration via the oral route, showing 99.5% activity and 9 days survival and showed low in vitro cytotoxicity. Pharmacokinetic studies in rats revealed good oral bioavailability (51% at 22 mg/kg) with a moderate rate of absorption, reasonable half-life (t_1/2 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. Toward toxicity profiling, 3 exhibited moderate potential to inhibit CYP1A2 (IC₅₀ = 1.5 渭M) and 2D6 (IC₅₀ = 0.4 渭M) as well as having a potential hERG liability (IC₅₀ = 3.7 渭M).