Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: part 1.
J Med Chem
; 57(6): 2789-98, 2014 Mar 27.
Article
de En
| MEDLINE
| ID: mdl-24568587
ABSTRACT
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Plasmodium
/
Protein kinases
/
Pyridazines
/
Inhibiteurs de protéines kinases
/
Imidazoles
/
Antipaludiques
Type d'étude:
Diagnostic_studies
/
Screening_studies
Limites:
Animals
Langue:
En
Journal:
J Med Chem
Sujet du journal:
QUIMICA
Année:
2014
Type de document:
Article
Pays d'affiliation:
République d'Afrique du Sud