3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential

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• 作者：Yassir Younis ; Frederic Douelle ; Tzu-Shean Feng ; Diego Gonz谩lez Cabrera ; Claire Le Manach ; Aloysius T. Nchinda ; Sandra Duffy ; Karen L. White ; David M. Shackleford ; Julia Morizzi ; Janne Mannila ; Kasiram Katneni ; Ravi Bhamidipati ; K. Mohammed Zabiulla ; Jayan T. Joseph ; Sridevi Bashyam ; David Waterson ; Michael J. Witty ; David Hardick ; Sergio Wittlin ; Vicky Avery ; Susan A. Charman ; Kelly Chibale
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3479-3487
• 全文大小：323K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure鈥揳ctivity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC₅₀ K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose鈥搑esponse studies generated ED₅₀ and ED₉₀ values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t_1/2 7鈥? h).