Optimization of pyrazolopyridine derivatives for the treatment of human African trypanosomiasis

Domain:

healthcare

Record type:

paper

Creator:

VinBenTylJiw

Publisher:

Ame

Host:

Despite recent advances in the development of therapeutics for human African trypanosomiasis, new treatments are needed to populate the drug pipeline in case of failure and resistance. A previously reported high throughput screen of human kinase inhibitors identified the pyrazolopyridine scaffold as an inhibitor of Trypanosoma brucei ( T.b .), which was subsequently optimized for antiparasitic activity. We report the structure-activity relationships (SAR) of the series, focused on improving antitrypanosomal activity and ADME properties, while using structure-based drug design (SBDD) to introduce parasite selectivity. Through these efforts, we identified analogs up to 11-fold more potent than the initial hits, and with up to 40-fold improvement in aqueous solubility. Selectivity for T. brucei over human kinases remains an area for improvement.

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