title: Characterization of in vivo metabolites of WR319691, a novel compound with activity against Plasmodium falciparum.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910-7500, USA, erin.milner@amedd.army.mil
authors.forename: Erin
authors.initials: E
authors.lastname: Milner
authors.forename: Jason
authors.initials: J
authors.lastname: Sousa
authors.forename: Brandon
authors.initials: B
authors.lastname: Pybus
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.forename: Sean
authors.initials: S
authors.lastname: Gardner
authors.forename: Kristina
authors.initials: K
authors.lastname: Grauer
authors.forename: Jay
authors.initials: J
authors.lastname: Moon
authors.forename: Dustin
authors.initials: D
authors.lastname: Carroll
authors.forename: Jennifer
authors.initials: J
authors.lastname: Auschwitz
authors.forename: Montip
authors.initials: M
authors.lastname: Gettayacamin
authors.forename: Patricia
authors.initials: P
authors.lastname: Lee
authors.forename: Susan
authors.initials: S
authors.lastname: Leed
authors.forename: William
authors.initials: W
authors.lastname: McCalmont
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.forename: Anchalee
authors.initials: A
authors.lastname: Tungtaeng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zeng
authors.forename: Michael
authors.initials: M
authors.lastname: Kozar
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Dow
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D011804:Quinolines; C568544:WR319691