Phosphodiesterase
10 (PDE10) inhibitors have
received much attention as promising
therapeutic agents for central nervous system (CNS) disorders such
as schizophrenia and Huntington’s disease. Recently, a hit
compound 1 with a novel chromone scaffold has shown moderate
inhibitory activity against PDE10A (IC50 = 500 nM). Hit-to-lead
optimization has resulted in compound 3e with an improved
inhibitory activity (IC50 = 6.5 nM), remarkable selectivity
(>95-fold over other PDEs), and good metabolic stability (RLM t
1/2 = 105 min) by using an integrated strategy
(molecular modeling, chemical synthesis, bioassay, and cocrystal structure).
The cocrystal structural information provides insights into the binding
pattern of 3e in the PDE10A catalytic domain to highlight
the key role of the halogen and hydrogen bonds toward Tyr524 and Tyr693,
respectively, thereby resulting in high selectivity against other
PDEs. These new observations are of benefit for the rational design
of the next generation PDE10 inhibitors for CNS disorders.
Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure–activity relationships (SAR) were explained with the assistance of molecular docking.
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