title: In vitro metabolism of phenoxypropoxybiguanide analogues in human liver microsomes to potent antimalarial dihydrotriazines.
abstract: Phenoxypropoxybiguanides, such as 1 (PS-15), are prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, 1a (WR99210), the active metabolite of 1, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Unfortunately, manufacturing processes and gastrointestinal intolerance have prevented the clinical development of 1. In vitro antimalarial activity and in vitro metabolism studies have been performed on newly synthesized phenoxypropoxybiguanide analogues. All of the active dihydrotriazine metabolites exhibited potent antimalarial activity with in vitro IC(50) values less than 0.04 ng/mL. In vitro metabolism studies in human liver microsomes identified the production of not only the active dihydrotriazine metabolite, but also a desalkylation on the carbonyl chain, and multiple hydroxylated metabolites. The V(max) for production of the active metabolites ranged from 10.8 to 27.7 pmol/min/mg protein with the K(m) ranging from 44.8 to 221 microM. The results of these studies will be used to guide the selection of a lead candidate.
authors.affiliation: Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland 20910, USA. todd.shearer@alcomlabs.com
authors.forename: Todd W
authors.initials: TW
authors.lastname: Shearer
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kozar
authors.forename: Michael T
authors.initials: MT
authors.lastname: O'Neil
authors.forename: Philip L
authors.initials: PL
authors.lastname: Smith
authors.forename: Guy A
authors.initials: GA
authors.lastname: Schiehser
authors.forename: David P
authors.initials: DP
authors.lastname: Jacobus
authors.forename: Damaris S
authors.initials: DS
authors.lastname: Diaz
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Yang
authors.forename: Wilbur K
authors.initials: WK
authors.lastname: Milhous
authors.forename: Donald R
authors.initials: DR
authors.lastname: Skillman
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001645:Biguanides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D001645:Biguanides; D005493:Folic Acid Antagonists; D011355:Prodrugs; D014227:Triazines