Salado, Irene G. Singh, Abhimanyu K. Moreno-Cinos, Carlos Sakaine, Guna Siderius, Marco Van der Veken, Pieter Matheeussen, An van der Meer, Tiffany Sadek, Payman Gul, Sheraz Maes, Louis Sterk, Geert-Jan Leurs, Rob Brown, David Augustyns, Koen Lead Optimization of Phthalazinone Phosphodiesterase Inhibitors as Novel Antitrypanosomal Compounds 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. 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
    https://acs.figshare.com/articles/dataset/Lead_Optimization_of_Phthalazinone_Phosphodiesterase_Inhibitors_as_Novel_Antitrypanosomal_Compounds/12033690
10.1021/acs.jmedchem.9b00985.s002