10.1021/acs.jmedchem.9b00985.s002
Irene
G. Salado
Irene
G.
Salado
Abhimanyu K. Singh
Abhimanyu K.
Singh
Carlos Moreno-Cinos
Carlos
Moreno-Cinos
Guna Sakaine
Guna
Sakaine
Marco Siderius
Marco
Siderius
Pieter Van der Veken
Pieter
Van der Veken
An Matheeussen
An
Matheeussen
Tiffany van der Meer
Tiffany
van der Meer
Payman Sadek
Payman
Sadek
Sheraz Gul
Sheraz
Gul
Louis Maes
Louis
Maes
Geert-Jan Sterk
Geert-Jan
Sterk
Rob Leurs
Rob
Leurs
David Brown
David
Brown
Koen Augustyns
Koen
Augustyns
Lead Optimization
of Phthalazinone Phosphodiesterase
Inhibitors as Novel Antitrypanosomal Compounds
American Chemical Society
2020
Novel Antitrypanosomal Compounds Human
phtalazinone derivatives
stability
TbrPDEB 1
Derivative 1
brucei
phenotypic screen
Compound 14
novel treatment
Compound 1
future efforts
vivo mouse disease model
TbrPDEB 1 inhibitor
Phthalazinone Phosphodiesterase Inhibitors
Lead Optimization
2020-03-26 08:43:21
Dataset
https://acs.figshare.com/articles/dataset/Lead_Optimization_of_Phthalazinone_Phosphodiesterase_Inhibitors_as_Novel_Antitrypanosomal_Compounds/12033690
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 <b>1</b> resulted in being a potent TbrPDEB1 inhibitor with interesting activity
against <i>T. brucei</i> in a phenotypic screen. Derivative <b>1</b> was studied in an acute <i>in vivo</i> 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 <i>T. brucei</i>. Compound <b>14</b> presented
a good microsomal stability in mouse and human microsomes and provides
a good starting point for future efforts.