JPC-2997, a new aminomethylphenol with high in vitro and in vivo antimalarial activities against blood stages of Plasmodium.

Autor:	Birrell GW; Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland, Australia., Chavchich M; Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland, Australia., Ager AL; University of Miami, Miami, Florida, USA., Shieh HM; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Heffernan GD; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Zhao W; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Krasucki PE; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Saionz KW; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Terpinski J; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Schiehser GA; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Jacobus LR; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Shanks GD; Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland, Australia., Jacobus DP; Jacobus Pharmaceutical Company, Princeton, New Jersey, USA., Edstein MD; Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland, Australia Mike.Edstein@defence.gov.au.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Jan; Vol. 59 (1), pp. 170-7. Date of Electronic Publication: 2014 Oct 20.
DOI:	10.1128/AAC.03762-14
Abstrakt:	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. (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu