Bland Nicholas D.

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Bland
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Nicholas D.
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  • Preprint
    Repurposing human PDE4 inhibitors for neglected tropical diseases : design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors
    ( 2014-07) Amata, Emanuele ; Bland, Nicholas D. ; Hoyt, Charles T. ; Settimo, Luca ; Campbell, Robert K. ; Pollastri, Michael P.
    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.
  • Preprint
    Synthesis and assessment of catechol diether compounds as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1)
    ( 2013-08-07) Woodring, Jennifer L. ; Bland, Nicholas D. ; Ochiana, Stefan O. ; Campbell, Robert K. ; Pollastri, Michael P.
    Human African trypanosomiasis (HAT) is a parasitic neglected tropical disease that affects 10,000 patients each year. Current treatments are sub-optimal, and the disease is fatal if not treated. Herein, we report our continuing efforts to repurpose the human phosphodiesterase 4 (hPDE4) inhibitor piclamilast to target trypanosomal phosphodiesterase TbrPDEB1. We prepared a range of substituted heterocyclic replacements for the 4-amino-3,5-dichloro-pyridine head group of piclamilast, and found that these compounds exhibited weak inhibitory activity of TbrPDEB1.
  • Preprint
    Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 1. Sildenafil analogs
    ( 2012-01) Wang, Cuihua ; Ashton, Trent D. ; Gustafson, Alden ; Bland, Nicholas D. ; Ochiana, Stefan O. ; Campbell, Robert K. ; Pollastri, Michael P.
    Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this report we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.
  • Preprint
    Evaluation of pyrrolidine and pyrazolone derivatives as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1)
    ( 2015-04-13) Amata, Emanuele ; Bland, Nicholas D. ; Campbell, Robert K. ; Pollastri, Michael P.
    Human African trypanosomiasis (HAT) is a parasitic disease, caused by the protozoan pathogen Trypanosoma brucei, which affects thousands every year and which is in need of new therapeutics. Herein we report the synthesis and assessment of a series of pyrrolidine and pyrazolone derivatives of human phosphodiesterase 4 (hPDE4) inhibitors for the assessment of their activity against the trypanosomal phosphodiesterase TbrPDEB1. The synthesized compounds showed weak potency against TbrPDEB1.
  • Preprint
    Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 2. Tadalafil analogs
    ( 2012-02-02) Ochiana, Stefan O. ; Gustafson, Alden ; Bland, Nicholas D. ; Wang, Cuihua ; Russo, Michael J. ; Campbell, Robert K. ; Pollastri, Michael P.
    In this report we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.