Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 1
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- 作者：Claire Le Manach ; Diego Gonz脿lez Cabrera ; Frederic Douelle ; Aloysius T. Nchinda ; Yassir Younis ; Dale Taylor ; Lubbe Wiesner ; Karen L. White ; Eileen Ryan ; Corinne March ; Sandra Duffy ; Vicky M. Avery ; David Waterson ; Michael J. Witty ; Sergio Wittlin ; Susan A. Charman ; Leslie J. Street ; Kelly Chibale
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：March 27, 2014
- 年：2014
- 卷：57
- 期：6
- 页码：2789-2798
- 全文大小：574K
- 年卷期：v.57,no.6(March 27, 2014)
- ISSN：1520-4804
文摘
A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure鈥揳ctivity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 脳 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.