Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 1

作者：Claire Le Manach, Diego González Cabrera, Frédèric 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 · 发表于：Journal of Medicinal Chemistry · 年份：2014 · DOI：10.1021/jm500098s · 被引用次数：48 · 研究领域：Quinazolinone synthesis and applications、Cancer therapeutics and mechanisms、Synthesis and biological activity

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-activity 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 × 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.