1580453-82-2Relevant academic research and scientific papers
Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a softfocus kinase library: Part 2
Le Manach, Claire,Paquet, Tanya,Gonzàlez Cabrera, Diego,Younis, Yassir,Taylor, Dale,Wiesner, Lubbe,Lawrence, Nina,Schwager, Sylva,Waterson, David,Witty, Michael J.,Wittlin, Sergio,Street, Leslie J.,Chibale, Kelly
, p. 8839 - 8848 (2014)
On the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po.
Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: Part 1
Le Manach, Claire,Gonzàlez Cabrera, Diego,Douelle, Frederic,Nchinda, Aloysius T.,Younis, Yassir,Taylor, Dale,Wiesner, Lubbe,White, Karen L.,Ryan, Eileen,March, Corinne,Duffy, Sandra,Avery, Vicky M.,Waterson, David,Witty, Michael J.,Wittlin, Sergio,Charman, Susan A.,Street, Leslie J.,Chibale, Kelly
, p. 2789 - 2798 (2014/04/17)
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 (IC 50: 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.
