Human African Trypanosomiasis (HAT) is a neglected tropical disease (NTD) caused by the parasite Trypanosoma brucei and affects nearly 70 million people that are at risk, with currently some 3,000 cases reported annually. We have previously reported that inhibition of an essential pair of enzymes in T. brucei, phosphodiesterase B1 and B2 (TbrPDEB1 and TbrPDEB2) leads to an increase in the cyclic adenosine monophosphate (cAMP) in the bloodstream form of the pathogen, which inhibits proliferation, blocks cytokinesis, and promotes parasite death. These trypanosomal enzymes exhibit 35% homology with human phosphodiesterase B4 (hPDE4B) but X-ray crystallography indicates variation in the binding region that could be leveraged for improved selectivity over human PDEs. In collaboration with GlaxoSmithKline, we performed a high-throughput screen that led to the identification of a series of pyrazolopyridines, and we have initiated initial structure activity relationship (SAR) studies. Guided by crystal structures with bound inhibitors we are working to decouple the hPDE activity and to promote selective binding to TbrPDE. Herein, the SAR of the pyrazolopyridine class will be discussed in conjunction with selectivity, absorption, distribution, metabolism, and excretion (ADME) properties.

SAR and ADME optimization of pyrazolopyridine-based human PDE4 inhibitors for human African trypanosomiasis

256th National Meeting (2018)

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