Details

Autor(en) / Beteiligte

• Zhang, Yong-Kang
• Plattner, Jacob J
• Easom, Eric E
• Jacobs, Robert T
• Guo, Denghui
• Freund, Yvonne R
• Berry, Pamela
• Ciaravino, Vic
• Erve, John C. L
• Rosenthal, Philip J
• Campo, Brice
• Gamo, Francisco-Javier
• Sanz, Laura M
• Cao, Jianxin

Titel

Benzoxaborole Antimalarial Agents. Part 5. Lead Optimization of Novel Amide Pyrazinyloxy Benzoxaboroles and Identification of a Preclinical Candidate

Ist Teil von

• Journal of medicinal chemistry, 2017-07, Vol.60 (13), p.5889-5908

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.