ABSTRACT
Ketotifen is known to exhibit antimalarial activity in mouse and monkey malaria models. However, the low plasma levels and short half life of the drug do not adequately explain its in vivo efficacy. We synthesized most of the known metabolites of ketotifen and evaluated their antimalarial activity and pharmacokinetics in mice. Norketotifen, the de-methylated metabolite of ketotifen, was a more potent antimalarial in vitro as compared to ketotifen, and exhibited equivalent activity in vivo against asexual blood and developing liver-stage parasites. After ketotifen dosing, norketotifen levels were much higher than ketotifen relative to the IC50s of the compounds against Plasmodium falciparum in vitro. The data support the notion that the antimalarial activity of ketotifen in mice is mediated through norketotifen.
Subject(s)
Antimalarials/pharmacology , Ketotifen/analogs & derivatives , Ketotifen/pharmacology , Malaria/drug therapy , Animals , Antimalarials/administration & dosage , Antimalarials/pharmacokinetics , Female , Humans , Inhibitory Concentration 50 , Ketotifen/administration & dosage , Ketotifen/pharmacokinetics , Liver/parasitology , Malaria/parasitology , Malaria, Falciparum/drug therapy , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Parasitic Sensitivity Tests , Plasmodium berghei/drug effects , Plasmodium berghei/isolation & purification , Plasmodium falciparum/drug effects , Plasmodium falciparum/isolation & purification , ProdrugsABSTRACT
A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The systematic variation of the 4-position amino alcohol side chain led to analogues that maintained potency while reducing accumulation in the central nervous system (CNS). Although the mechanism of action remains elusive, these data indicate that the 4-position side chain is critical for activity and that potency (as measured by IC(90)) does not correlate with accumulation in the CNS. A new lead compound, (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol (WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria treatments currently approved for mefloquine.
Subject(s)
Antimalarials/chemical synthesis , Ethanolamines/chemical synthesis , Malaria/prevention & control , Methanol/analogs & derivatives , Methanol/chemical synthesis , Plasmodium falciparum/drug effects , Quinolines/chemical synthesis , Animals , Antimalarials/pharmacology , Cell Line , Cell Membrane Permeability , Dimerization , Dogs , Drug Resistance , Ethanolamines/pharmacology , Ethylenediamines/chemical synthesis , Ethylenediamines/pharmacology , Mefloquine/analogs & derivatives , Mefloquine/chemical synthesis , Mefloquine/pharmacology , Methanol/pharmacology , Mice , Plasmodium berghei , Quinolines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
WR319691 has been shown to exhibit reasonable Plasmodium falciparum potency in vitro and exhibits reduced permeability across MDCK cell monolayers, which as part of our screening cascade led to further in vivo analysis. Single-dose pharmacokinetics was evaluated after an IV dose of 5 mg/kg in mice. Maximum bound and unbound brain levels of WR319691 were 97 and 0.05 ng/g versus approximately 1,600 and 3.2 ng/g for mefloquine. The half-life of WR319691 in plasma was approximately 13 h versus 23 h for mefloquine. The pharmacokinetics of several N-dealkylated metabolites was also evaluated. Five of six of these metabolites were detected and maximum total and free brain levels were all lower after an IV dose of 5 mg/kg WR319691 compared to mefloquine at the same dose. These data provide proof of concept that it is feasible to substantially lower the brain levels of a 4-position modified quinoline methanol in vivo without substantially decreasing potency against P. falciparum in vitro.
