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Basic Information
ID: ALA4321871
Journal: J Med Chem
Title: Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis.
Authors: Tear WF, Bag S, Diaz-Gonzalez R, Ceballos-Pérez G, Rojas-Barros DI, Cordon-Obras C, Pérez-Moreno G, García-Hernández R, Martinez-Martinez MS, Ruiz-Perez LM, Gamarro F, Gonzalez Pacanowska D, Caffrey CR, Ferrins L, Manzano P, Navarro M, Pollastri MP.
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.
CiteXplore: 31846577
DOI: 10.1021/acs.jmedchem.9b01741
Patent ID: ┄
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