Artefenomel [4-(2-{4-[(1s,1''R,3''S,4s,5'r,5''S,7''S)-Dispiro[cyclohexane-1,3'-[1,2,4]trioxolane-5',2''-tricyclo[3.3.1.13,7]decan]-4-yl]phenoxy}ethyl)morpholine]
is a synthetic peroxide antimalarial drug candidate designed to provide a
single-dose oral cure in humans. The outstanding efficacy and prolonged blood
concentrations of Artefenomel are the result of a design strategy that
stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby
reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit
parasite death. In vitro, Artefenomel
is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC50 values comparable
to those for the clinically used artemisinin derivatives. Unlike all other
synthetic peroxides and semisynthetic artemisinin derivatives, Artefenomel
completely cures Plasmodium berghei-infected
mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity
superior to that of the benchmark chemoprophylactic agent, Mefloquine. Compared
with other peroxide-containing antimalarial agents, such as the artemisinin
derivatives and the first-generation ozonide OZ277, Artefenomel exhibits a
substantial increase in the pharmacokinetic half-life and blood concentration
versus time profile in three preclinical species. These exceptional
antimalarial and pharmacokinetic properties led to its selection as a clinical
drug development candidate. Artefenomel has successfully completed Phase I
clinical trials, where it was shown to be safe at doses up to 1,600 mg and is
currently undergoing Phase IIa trials in malaria patients [1].
References:
1. Charma, S. A.; et. al. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proc Natl Acad Sci U S A 2011, 108(11), 4400-4405.
