FR-900098, an antimalarial development candidate that inhibits the non-mevalonate isoprenoid biosynthesis pathway, shows no evidence of acute toxicity and genotoxicity

ABSTRACT

FR-900098 is an inhibitor of 1-deoxy-d-xylulose-5-phosphate (DXP) reductoisomerase, the second enzyme in the non-mevalonate isoprenoid biosynthesis pathway. In previous studies, FR-900098 was shown to possess potent antimalarial activity in vitro and in a murine malaria model. In order to provide a basis for further preclinical and clinical development, we studied the acute toxicity and genotoxicity of FR-900098. We observed no acute toxicity in rats, i.e. there were no clinical signs of toxicity and no substance-related deaths after the administration of a single dose of 3000 mg/kg body weight orally or 400 mg/kg body weight intravenously. No mutagenic potential was detected in the Salmonella typhimurium reverse mutation assay (Ames test) or an in vitro mammalian cell gene mutation test using mouse lymphoma L5178Y/TK^+/− cells (clone 3.7.2C), both with and without metabolic activation. In addition, FR-900098 demonstrated no clastogenic or aneugenic capability or significant adverse effects on blood formation in an in vivo micronucleus test with bone marrow erythrocytes from NMRI mice. We conclude that FR-900098 lacks acute toxicity and genotoxicity, supporting its further development as an antimalarial drug.

KEYWORDS:

• acute toxicity
• Ames test
• drug development
• fosmidomycin
• FR-900098
• genotoxicity
• malaria
• micronucleus test
• mouse lymphoma assay
• Plasmodium falciparum

Abbreviations

CP	=	cyclophosphamide monohydrate
DMSO	=	dimethyl sulfoxide
DXP	=	1-deoxy-d-xylulose-5-phosphate
GLP	=	good laboratory practice
ICH	=	International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
i.v.	=	intravenously
MF	=	mutant frequency
MLA	=	mouse lymphoma assay
MMS	=	methyl methanesulfonate
NCE	=	normochromatic erythrocytes
OECD	=	Organization for Economic Cooperation and Development
PCE	=	polychromatic erythrocytes
PE	=	plating efficiency
p.o.	=	orally
RBC	=	red blood cells
RTG	=	relative total growth
SG	=	suspension growth
TFT	=	trifluorothymidine
TK	=	thymidine kinase

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors thank Dr. Richard M. Twyman and Dr. David Hutchinson for editing the manuscript.

Additional information

Funding

This work was supported by a grant from the European Commission (Development of New Drugs for the treatment of Malaria, Integrated Project #018834) to H.J. and M.S. and by the excellence initiative of the Hessian Ministry of Science, Higher Education and Art, which encompasses a generous grant for the LOEWE Center for ‘Insect Biotechnology and Bioresources’ to A.V.