Abstract
Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Animals
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Binding Sites
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Cell Line
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Cysteine Endopeptidases / chemistry
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / pharmacokinetics
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Cysteine Proteinase Inhibitors / therapeutic use*
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Cysteine Proteinase Inhibitors / toxicity
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Dipeptides / chemical synthesis
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Dipeptides / pharmacokinetics
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Dipeptides / therapeutic use*
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Dipeptides / toxicity
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Drug Design
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Female
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Humans
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Leishmania donovani / drug effects
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Ligands
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Mice
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Microsomes, Liver / metabolism
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Molecular Structure
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Nitriles / chemical synthesis
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Nitriles / pharmacokinetics
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Nitriles / therapeutic use*
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Nitriles / toxicity
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Plasmodium falciparum / drug effects
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Protozoan Proteins / antagonists & inhibitors
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Protozoan Proteins / chemistry
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Rats
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Structure-Activity Relationship
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Swine
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Triazoles / chemical synthesis
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Triazoles / pharmacokinetics
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Triazoles / therapeutic use*
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Triazoles / toxicity
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / pharmacokinetics
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Trypanocidal Agents / therapeutic use*
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Trypanocidal Agents / toxicity
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Trypanosoma brucei rhodesiense / drug effects
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Trypanosoma cruzi / drug effects
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Cysteine Proteinase Inhibitors
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Dipeptides
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Ligands
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Nitriles
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Protozoan Proteins
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Triazoles
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Trypanocidal Agents
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Cysteine Endopeptidases
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rhodesain