ABSTRACT
The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.
Subject(s)
Leishmaniasis, Visceral/drug therapy , Morpholines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Trypanocidal Agents/therapeutic use , Animals , Female , Hep G2 Cells , Humans , Leishmania donovani/drug effects , Male , Mice, Inbred BALB C , Molecular Structure , Morpholines/chemical synthesis , Morpholines/toxicity , Parasitic Sensitivity Tests , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/toxicity , Pyrazoles/chemical synthesis , Pyrazoles/toxicity , Pyrimidines/chemical synthesis , Pyrimidines/toxicity , Rats, Sprague-Dawley , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/toxicityABSTRACT
On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.
Subject(s)
Aminoquinolines/chemical synthesis , Amodiaquine/analogs & derivatives , Amodiaquine/chemical synthesis , Antimalarials/chemical synthesis , Aminoquinolines/pharmacokinetics , Aminoquinolines/pharmacology , Amodiaquine/chemistry , Amodiaquine/pharmacokinetics , Amodiaquine/pharmacology , Animals , Antimalarials/pharmacokinetics , Antimalarials/pharmacology , Cell Survival , Chloroquine/pharmacology , Dogs , Drug Resistance , Female , Haplorhini , Hepatocytes/cytology , Hepatocytes/drug effects , Humans , In Vitro Techniques , Malaria/drug therapy , Malaria/parasitology , Male , Mice , Parasitic Sensitivity Tests , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Plasmodium yoelii/drug effects , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
N-tert-Butyl isoquine (4) (GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.
