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ID: ALA4665888
Journal: J Med Chem
Title: [1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration.
Authors: Tresadern G,Velter I,Trabanco AA,Van den Keybus F,Macdonald GJ,Somers MVF,Vanhoof G,Leonard PM,Lamers MBAC,Van Roosbroeck YEM,Buijnsters PJJA
Abstract: We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5-a]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC's from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC of 1.3 ± 0.39 nM, ∼100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.
CiteXplore: 33105987