Hit-to-Lead Optimization of Benzoxazepinoindazoles As Human African Trypanosomiasis Therapeutics

Human African trypanosomiasis (HAT) is a neglected tropical disease caused by infection with either of two subspecies of the parasite Trypanosoma brucei. Due to a lack of economic incentive to develop new drugs, current treatments have severe limitations in terms of safety, efficacy, and ease of adm...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 63; no. 5; pp. 2527 - 2546
Main Authors:	Klug, Dana M, Tschiegg, Laura, Diaz, Rosario, Rojas-Barros, Domingo, Perez-Moreno, Guiomar, Ceballos, Gloria, García-Hernández, Raquel, Martinez-Martinez, Maria Santos, Manzano, Pilar, Ruiz, Luis Miguel, Caffrey, Conor R, Gamarro, Francisco, Pacanowska, Dolores Gonzalez, Ferrins, Lori, Navarro, Miguel, Pollastri, Michael P
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 12-03-2020
Online Access:	Get full text
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Summary:	Human African trypanosomiasis (HAT) is a neglected tropical disease caused by infection with either of two subspecies of the parasite Trypanosoma brucei. Due to a lack of economic incentive to develop new drugs, current treatments have severe limitations in terms of safety, efficacy, and ease of administration. In an effort to develop new HAT therapeutics, we report the structure–activity relationships around T. brucei for a series of benzoxazepinoindazoles previously identified through a high-throughput screen of human kinase inhibitors, and the subsequent in vivo experiments for HAT. We identified compound 18, which showed an improved kinase selectivity profile and acceptable pharmacokinetic parameters, as a promising lead. Although treatment with 18 cured 60% of mice in a systemic model of HAT, the compound was unable to clear parasitemia in a CNS model of the disease. We also report the results of cross-screening these compounds against T. cruzi, L. donovani, and S. mansoni.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.9b01506