Lead Optimization
of Phthalazinone Phosphodiesterase
Inhibitors as Novel Antitrypanosomal Compounds
Posted on 2020-03-26 - 08:43
Human
African trypanosomiasis is causing thousands of deaths every
year in the rural areas of Africa. In this manuscript we describe
the optimization of a family of phtalazinone derivatives. Phosphodiesterases
have emerged as attractive molecular targets for a novel treatment
for a variety of neglected parasitic diseases. Compound 1 resulted in being a potent TbrPDEB1 inhibitor with interesting activity
against T. brucei in a phenotypic screen. Derivative 1 was studied in an acute in vivo mouse disease
model but unfortunately showed no efficacy due to low metabolic stability.
We report structural modifications to achieve compounds with an improved
metabolic stability while maintaining high potency against TbrPDEB1
and T. brucei. Compound 14 presented
a good microsomal stability in mouse and human microsomes and provides
a good starting point for future efforts.
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Salado, Irene
G.; Singh, Abhimanyu K.; Moreno-Cinos, Carlos; Sakaine, Guna; Siderius, Marco; Van der Veken, Pieter; et al. (2020). Lead Optimization
of Phthalazinone Phosphodiesterase
Inhibitors as Novel Antitrypanosomal Compounds. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.9b00985
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AUTHORS (15)
IS
Irene
G. Salado
AS
Abhimanyu K. Singh
CM
Carlos Moreno-Cinos
GS
Guna Sakaine
MS
Marco Siderius
PV
Pieter Van der Veken
AM
An Matheeussen
Tv
Tiffany van der Meer
PS
Payman Sadek
SG
Sheraz Gul
LM
Louis Maes
GS
Geert-Jan Sterk
RL
Rob Leurs
DB
David Brown
KA
Koen Augustyns