title: Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Reduction 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.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA. geoffrey.dow@us.army.mil
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Dow
authors.forename: Erin
authors.initials: E
authors.lastname: Milner
authors.forename: Ian
authors.initials: I
authors.lastname: Bathurst
authors.forename: Jayendra
authors.initials: J
authors.lastname: Bhonsle
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.forename: Sean
authors.initials: S
authors.lastname: Gardner
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.forename: Michael
authors.initials: M
authors.lastname: Kozar
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lanteri
authors.forename: Anne
authors.initials: A
authors.lastname: Mannila
authors.forename: William
authors.initials: W
authors.lastname: McCalmont
authors.forename: Jay
authors.initials: J
authors.lastname: Moon
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.forename: Norma
authors.initials: N
authors.lastname: Roncal
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Jason
authors.initials: J
authors.lastname: Sousa
authors.forename: Jessica
authors.initials: J
authors.lastname: Steuten
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zeng
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002490:Central Nervous System / Q000737:chemistry*; D007275:Injections, Intravenous; D008297:Male; D015767:Mefloquine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051379:Mice; D010949:Plasma / Q000737:chemistry; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D000962:Antimalarials; D011804:Quinolines; C037219:quinoline; D015767:Mefloquine