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Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2020-01-08 , DOI: 10.1021/acs.jmedchem.9b01741
Westley F Tear 1 , Seema Bag 1 , Rosario Diaz-Gonzalez 2 , Gloria Ceballos-Pérez 2 , Domingo I Rojas-Barros 2 , Carlos Cordon-Obras 2 , Guiomar Pérez-Moreno 2 , Raquel García-Hernández 2 , Maria Santos Martinez-Martinez 3 , Luis Miguel Ruiz-Perez 2 , Francisco Gamarro 2 , Dolores Gonzalez Pacanowska 2 , Conor R Caffrey 4 , Lori Ferrins 1 , Pilar Manzano 3 , Miguel Navarro 2 , Michael P Pollastri 1
Affiliation  

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.

中文翻译:

重组吡唑并[1,5-b]哒嗪用于治疗非洲锥虫病的选择性和理化优化。

从42 444种已知的人类激酶抑制剂的高通量筛选中,确定了吡唑并[1,5-b]哒嗪支架可以开始优化用于治疗非洲锥虫病。先前报道的针对人类激酶的类似化合物的数据利用GSK-3β,CDK-2和CDK-4来尝试改善该系列的选择性,导致23a对T.b表现出选择性。布鲁斯对这三种人类酶的研究。同时,优化了已知影响该系列吸收,分布,代谢和排泄(ADME)分布的特性,从而使20g进入小鼠功效研究。尽管20克对小鼠具有毒性,但在PK研究中它也证明了中枢神经系统的渗透,并且六只小鼠中有四只明显降低了寄生虫病。
更新日期:2020-01-08
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