{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Tear WF"],"funding":["National Institute of Allergy and Infectious Diseases","NIAID NIH HHS","Ministerio de Econom?a, Industria y Competitividad, Gobierno de Espa?a","Bill and Melinda Gates Foundation"],"pagination":["756-783"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6985937"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["63(2)"],"pubmed_abstract":["From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-<i>b</i>]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 <b>23a</b> which showed selectivity for <i>T. b. brucei</i> 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 <b>20g</b> being progressed into an efficacy study in mice. Though <b>20g</b> showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant redu"],"journal":["Journal of medicinal chemistry"],"pubmed_title":["Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-<i>b</i>]pyridazines for the Treatment of Human African Trypanosomiasis."],"pmcid":["PMC6985937"],"funding_grant_id":["R56AI099476","R01AI114685","RD16/0027/0019","R21 AI126296","R21 AI127594","SAF2016-79957-R","RD16/0027/0014","R01 AI082577","R01AI082577","R21AI127594","R21AI126296","R01AI124046","R01 AI114685","SAF2015-71444-P","R01 AI124046","OPP1171488","R56 AI099476"],"pubmed_authors":["Martinez-Martinez MS","Pollastri MP","Ruiz-Perez LM","Rojas-Barros DI","Ferrins L","Caffrey CR","Perez-Moreno G","Gamarro F","Navarro M","Bag S","Ceballos-Perez G","Diaz-Gonzalez R","Gonzalez Pacanowska D","Cordon-Obras C","Garcia-Hernandez R","Manzano P","Tear WF"],"additional_accession":[]},"is_claimable":false,"name":"Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-<i>b</i>]pyridazines for the Treatment of Human African Trypanosomiasis.","description":"From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-<i>b</i>]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 <b>23a</b> which showed selectivity for <i>T. b. brucei</i> 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 <b>20g</b> being progressed into an efficacy study in mice. Though <b>20g</b> showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant redu","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jan","modification":"2026-05-07T00:42:20.879Z","creation":"2020-05-22T08:35:37Z"},"accession":"S-EPMC6985937","cross_references":{"pubmed":["31846577"],"doi":["10.1021/acs.jmedchem.9b01741"]}}