Development of a new generation of 4-aminoquinoline antimalarial compounds using predictive pharmacokinetic and toxicology models.
Among the known antimalarial drugs, chloroquine (CQ) and other 4-aminoquinolines have shown high potency and good bioavailability. Yet complications associated with drug resistance necessitate the discovery of effective new antimalarial agents. ADMET prediction studies were employed to evaluate a library of new molecules based on the 4-aminoquinolone-related structure of CQ. Extensive in vitro screening and in vivo pharmacokinetic studies in mice helped to identify two lead molecules, 18 and 4, with promising in vitro therapeutic efficacy, improved ADMET properties, low risk for drug-drug interactions, and desirable pharmacokinetic profiles. Both 18 and 4 are highly potent antimalarial compounds, with IC(50) values of 5.6 and 17.3 nM, respectively, against the W2 (CQ-resistant) strain of Plasmodium falciparum (for CQ, IC(50) = 382 nM). When tested in mice, these compounds were found to have biological half-lives and plasma exposure values similar to or higher than those of CQ; they are therefore desirable candidates to pursue in future clinical trials.
Ray
Sunetra
S
SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025, USA.
Madrid
Peter B
PB
Catz
Paul
P
LeValley
Susanna E
SE
Furniss
Michael J
MJ
Rausch
Linda L
LL
Guy
R Kiplin
RK
DeRisi
Joseph L
JL
Iyer
Lalitha V
LV
Green
Carol E
CE
Mirsalis
Jon C
JC
D000634:Aminoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D051379:Mice; D010599:Pharmacokinetics; D010963:Plasmodium falciparum / Q000187:drug effects; D054852:Small Molecule Libraries; D014116:Toxicology
D000634:Aminoquinolines; D000962:Antimalarials; D054852:Small Molecule Libraries; C001920:4-aminoquinoline