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Publication Abstract from PubMed

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 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, approximately 100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.

[1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration.,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 J Med Chem. 2020 Oct 26. doi: 10.1021/acs.jmedchem.0c01272. PMID:33105987^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.