Abstract
From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold was identified to begin optimization for the treatment of human African trypanosomiasis. Previously reported data for analogous compounds against human kinases GSK-3β, CDK-2, and CDK-4 were leveraged to try to improve the selectivity of the series, resulting in 23a which showed selectivity for T. b. brucei over these three human enzymes. In parallel, properties known to influence the absorption, distribution, metabolism, and excretion (ADME) profile of the series were optimized resulting in 20g being progressed into an efficacy study in mice. Though 20g showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant reduction of parasitemia in four out of the six mice.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Survival / drug effects
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Crystallography, X-Ray
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Drug Repositioning
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Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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High-Throughput Screening Assays
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Humans
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Leishmania donovani / drug effects
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Mice
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Models, Molecular
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Pyridazines / chemical synthesis*
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Pyridazines / pharmacokinetics
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Pyridazines / pharmacology*
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Rats
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Structure-Activity Relationship
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Substrate Specificity
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Tissue Distribution
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Trypanocidal Agents / chemical synthesis*
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Trypanocidal Agents / pharmacokinetics
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Trypanocidal Agents / pharmacology*
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Trypanosoma brucei brucei / drug effects
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Trypanosomiasis, African / drug therapy*
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Trypanosomiasis, African / parasitology
Substances
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Pyridazines
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Trypanocidal Agents
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Glycogen Synthase Kinase 3 beta
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CDK2 protein, human
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CDK4 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4