A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides.

Autor:	Keurulainen L; †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland., Vahermo M; †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland., Puente-Felipe M; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Sandoval-Izquierdo E; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Crespo-Fernández B; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Guijarro-López L; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Huertas-Valentín L; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., de las Heras-Dueña L; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Leino TO; †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland., Siiskonen A; †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland., Ballell-Pages L; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Sanz LM; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Castañeda-Casado P; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Jiménez-Díaz MB; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Martínez-Martínez MS; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Viera S; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Kiuru P; †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland., Calderón F; ‡Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain., Yli-Kauhaluoma J; †Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki, Viikinkaari 5 E (P.O. Box 56), FI-00014 Helsinki, Finland.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2015 Jun 11; Vol. 58 (11), pp. 4573-80. Date of Electronic Publication: 2015 May 19.
DOI:	10.1021/acs.jmedchem.5b00114
Abstrakt:	Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.
Databáze:	MEDLINE
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