Advice on Phosphodiesterase (PDE) Inhibitor Optimization for HAT Drug Development

Status
Completed
Start date
End date
Start stage
Hit to lead
End stage
Hit to lead
Disease
Human African trypanosomiasis (HAT)
Research areas
Drug

Phosphodiesterases (PDEs) are important regulators of cell signal transduction, and PDE inhibitors have been developed to treat various diseases, such as erectile dysfunction and chronic obstructive pulmonary disease (COPD). After reading reports that PDE inhibition in T. brucei, which causes HAT, led to parasite death, Dr. Pollastri and colleagues screened existing human PDE inhibitors for activity against T. brucei PDEs. When the team examined the inhibitors’ structure-activity relationships (SAR) — correlations between compound structures and activity against parasite PDEs —, it was difficult to discern clear trends or patterns, which slowed the compound optimization process significantly. BVGH connected Dr. Pollastri with scientists at Eisai who had experience working with PDE inhibitors. The scientists provided Dr. Pollastri with valuable advice on compound optimization, including suggestions for future approaches and experiments.