Lead Optimization
of Phthalazinone Phosphodiesterase
Inhibitors as Novel Antitrypanosomal Compounds
Irene
G. Salado
Abhimanyu K. Singh
Carlos Moreno-Cinos
Guna Sakaine
Marco Siderius
Pieter Van der Veken
An Matheeussen
Tiffany van der Meer
Payman Sadek
Sheraz Gul
Louis Maes
Geert-Jan Sterk
Rob Leurs
David Brown
Koen Augustyns
10.1021/acs.jmedchem.9b00985.s001
https://acs.figshare.com/articles/journal_contribution/Lead_Optimization_of_Phthalazinone_Phosphodiesterase_Inhibitors_as_Novel_Antitrypanosomal_Compounds/12033687
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.
2020-03-26 08:43:20
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