Tresadern, Gary; Velter, Ingrid; Trabanco, Andres A.; Van den Keybus, Frans; Macdonald, Gregor J.; Somers, Marijke V. F.; Vanhoof, Greet; Leonard, Philip M.; Lamers, Marieke B. A. C.; Van Roosbroeck, Yves E. M.; Buijnsters, Peter J. J. A. published the artcile< [1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration>, Formula: C8H9NO2, the main research area is triazolopyrimidine preparation selective PDE2A inhibitor; structure triazolopyrimidine inhibition phosphodiesterase selectivity; pharmacokinetics CYP inhibition BBB permeability triazolopyrimidine; free energy perturbation optimization triazolopyrimidine substituent phosphodiesterase inhibitor; crystal structure triazolopyrimidine complex phosphodiesterase 2A.
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 crystallog. 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 chem. 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 mols. with IC50’s from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC50 of 1.3 ± 0.39 nM, ~100-fold selectivity vs. other PDE enzymes, clean cytochrome P 450 profile, in vivo target occupancy, and promise for further lead optimization.
Journal of Medicinal Chemistry published new progress about Biological permeation. 33402-75-4 belongs to class esters-buliding-blocks, and the molecular formula is C8H9NO2, Formula: C8H9NO2.
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