Development of a New Generation of 4-Aminoquinoline Antimalarial Compounds Using Predictive Pharmacokinetic and Toxicology Models

• Published in: Journal of medicinal chemistry 2010-05, Vol.53 (9), p.3685-3695
• Main Authors: Ray, Sunetra, Madrid, Peter B, Catz, Paul, LeValley, Susanna E, Furniss, Michael J, Rausch, Linda L, Guy, R. Kiplin, DeRisi, Joseph L, Iyer, Lalitha V, Green, Carol E, Mirsalis, Jon C
• Format: Article
• Language: English
• Subjects: Aminoquinolines - pharmacology; Aminoquinolines - therapeutic use; Animals; Antimalarials - chemistry; Antimalarials - pharmacology; Drug Evaluation, Preclinical; Half-Life; Mice; Pharmacokinetics; Plasmodium falciparum - drug effects; Small Molecule Libraries; Toxicology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100057h

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 IC50 values of 5.6 and 17.3 nM, respectively, against the W2 (CQ-resistant) strain of Plasmodium falciparum (for CQ, IC50 = 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.