Abstract
BackgroundThe clinical use of mefloquine (MQ) has declined due to dose-related neurological events. Next generation quinoline methanols (NGQMs) that do not accumulate in the central nervous system (CNS) to the same extent may have utility. In this study, CNS levels of NGQMs relative to MQ were measured and an early lead chemotype was identified for further optimization.Experimental designThe plasma and brain levels of MQ and twenty five, 4-position modified NGQMs were determined using LCMS/MS at 5 min, 1, 6 and 24 h after IV administration (5 mg/kg) to male FVB mice. Fraction unbound in brain tissue homogenate was assessed in vitro using equilibrium dialysis and this was then used to calculate brain-unbound concentration from the measured brain total concentration. A five-fold reduction CNS levels relative to mefloquine was considered acceptable. Additional pharmacological properties such as permeability and potency were determined.ResultsThe maximum brain (whole/free) concentrations of MQ were 1807/4.9 ng/g. Maximum whole brain concentrations of NGQMs were 23 - 21546 ng/g. Maximum free brain concentrations were 0.5 to 267 ng/g. Seven (28%) and two (8%) compounds exhibited acceptable whole and free brain concentrations, respectively. Optimization of maximum free brain levels, IC90s (as a measure or potency) and residual plasma concentrations at 24 h (as a surrogate for half-life) in the same molecule may be feasible since they were not correlated. Diamine quinoline methanols were the most promising lead compounds.ConclusionReduction of CNS levels of NGQMs relative to mefloquine may be feasible. Optimization of this property together with potency and long half-life may be feasible amongst diamine quinoline methanols.
Highlights
The clinical use of mefloquine (MQ) has declined due to dose-related neurological events
Reduction of central nervous system (CNS) levels of Next generation quinoline methanols (NGQMs) relative to mefloquine may be feasible. Optimization of this property together with potency and long half-life may be feasible amongst diamine quinoline methanols
Mefloquine exhibits two of these characteristics, but will likely not find use as an intermittent preventive treatment (IPT) drug because of the adverse CNS events observed at the treatment level doses [4] that may be required for IPT
Summary
The clinical use of mefloquine (MQ) has declined due to dose-related neurological events. Mefloquine exhibits two of these characteristics, but will likely not find use as an IPT drug because of the adverse CNS events observed at the treatment level doses [4] that may be required for IPT. This would presumably not be an issue for generation analogs of mefloquine without such a liability. The goal is to identify a lead compound for IPT, based on a mefloquine scaffold, for which accumulation into the CNS is substantially reduced Such a compound should have an improved CNS safety profile relative to mefloquine
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