Repurposing human PDE4 inhibitors for neglected tropical diseases: design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors.

Emanuele Amata, Nicholas D Bland, Charles T Hoyt, Luca Settimo, Robert K Campbell, Michael P Pollastri

Bioorganic & medicinal chemistry letters 2014 Sep 01

filter terms:

A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the parasite which causes African sleeping sickness, a neglected tropical disease that affects thousands each year, and TbrPDEB1 has been shown to be an essential target of therapeutic relevance. Noting that 1 is a weak inhibitor of TbrPDEB1, we report the design and synthesis of analogs of this compound, culminating in 12b, a sub-micromolar inhibitor of TbrPDEB1 that shows modest inhibition of T. brucei proliferation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Citation

Emanuele Amata, Nicholas D Bland, Charles T Hoyt, Luca Settimo, Robert K Campbell, Michael P Pollastri. Repurposing human PDE4 inhibitors for neglected tropical diseases: design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors. Bioorganic & medicinal chemistry letters. 2014 Sep 01;24(17):4084-9