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 (IC
50s
) ranging from 7 nM to 34 nM. JPC-2997 is >2,500 times less cytotoxic (IC
50
s > 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 (ED
50
) 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.
