title: JPC-2997, a new aminomethylphenol with high in vitro and in vivo antimalarial activities against blood stages of Plasmodium.
abstract: 4-(tert-Butyl)-2-((tert-butylamino)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)-phenol (JPC-2997) is a new aminomethylphenol compound that is highly active in vitro against the chloroquine-sensitive D6, the chloroquine-resistant W2, and the multidrug-resistant TM90-C2B Plasmodium falciparum lines, with 50% inhibitory concentrations (IC50s) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC50s > 35 μM) to human (HepG2 and HEK293) and rodent (BHK) cell lines than the D6 parasite line. In comparison to the chemically related WR-194,965, a drug that had advanced to clinical studies, JPC-2997 was 2-fold more active in vitro against P. falciparum lines and 3-fold less cytotoxic. The compound possesses potent in vivo suppression activity against Plasmodium berghei, with a 50% effective dose (ED50) of 0.5 mg/kg of body weight/day following oral dosing in the Peters 4-day test. The radical curative dose of JPC-2997 was remarkably low, at a total dose of 24 mg/kg, using the modified Thompson test. JPC-2997 was effective in curing three Aotus monkeys infected with a chloroquine- and pyrimethamine-resistant strain of Plasmodium vivax at a dose of 20 mg/kg daily for 3 days. At the doses administered, JPC-2997 appeared to be well tolerated in mice and monkeys. Preliminary studies of JPC-2997 in mice show linear pharmacokinetics over the range 2.5 to 40 mg/kg, a low clearance of 0.22 liters/h/kg, a volume of distribution of 15.6 liters/kg, and an elimination half-life of 49.8 h. The high in vivo potency data and lengthy elimination half-life of JPC-2997 suggest that it is worthy of further preclinical assessment as a partner drug.
authors.affiliation: Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland, Australia.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Birrell
authors.affiliation: Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Chavchich
authors.affiliation: University of Miami, Miami, Florida, USA.
authors.forename: Arba L
authors.initials: AL
authors.lastname: Ager
authors.affiliation: Jacobus Pharmaceutical Company, Princeton, New Jersey, USA.
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Shieh
authors.affiliation: Jacobus Pharmaceutical Company, Princeton, New Jersey, USA.
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Heffernan
authors.affiliation: Jacobus Pharmaceutical Company, Princeton, New Jersey, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Jacobus Pharmaceutical Company, Princeton, New Jersey, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Krasucki
authors.affiliation: Jacobus Pharmaceutical Company, Princeton, New Jersey, USA.
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Saionz
authors.affiliation: Jacobus Pharmaceutical Company, Princeton, New Jersey, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Terpinski
authors.affiliation: Jacobus Pharmaceutical Company, Princeton, New Jersey, USA.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Schiehser
authors.affiliation: Jacobus Pharmaceutical Company, Princeton, New Jersey, USA.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Jacobus
authors.affiliation: Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland, Australia.
authors.forename: G Dennis
authors.initials: GD
authors.lastname: Shanks
authors.affiliation: Jacobus Pharmaceutical Company, Princeton, New Jersey, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Jacobus
authors.affiliation: Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland, Australia Mike.Edstein@defence.gov.au.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Edstein
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016645:Aotidae; D002460:Cell Line; D006224:Cricetinae; D004351:Drug Resistance; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010636:Phenols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects*; D010966:Plasmodium vivax / Q000187:drug effects; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; C000600814:JPC-2997; D010636:Phenols; D011725:Pyridines