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Title

Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis

AuthorsTear, WF; Bag S; Diaz-Gonzalez, R; Ceballos-Pérez, G; Rojas-Barros, Domingo I.; Cordon-Obras, Carlos; Pérez-Moreno, G; García-Hernández, R; Martinez-Martinez, MS; Ruiz-Pérez, Luis Miguel; Gamarro, Francisco; González- Pacanowska, D.; Caffrey, CR; Ferrins, L; Manzano, P; Navarro, M.; Pollastri, MP
Issue Date2020
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 63: 756- 783 (2020)
AbstractFrom a high-throughput screen of 42 444 knownhuman kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold wasidentified to begin optimization for the treatment of human Africantrypanosomiasis. Previously reported data for analogous com-pounds against human kinases GSK-3β, CDK-2, and CDK-4 wereleveraged to try to improve the selectivity of the series, resulting in23awhich showed selectivity forT. b. bruceiover these threehuman enzymes. In parallel, properties known to influence theabsorption, distribution, metabolism, and excretion (ADME)profile of the series were optimized resulting in20gbeingprogressed into an efficacy study in mice. Though20gshowedtoxicity in mice, it also demonstrated CNS penetration in a PKstudy and significant reduction of parasitemia in four out of the sixmice.
URIhttp://hdl.handle.net/10261/213997
DOIhttp://dx.doi.org/10.1021/acs.jmedchem.9b01741
Identifiersdoi: 10.1021/acs.jmedchem.9b01741
issn: 0022-2623
e-issn: 1520-4804
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