2. Academic Validation
  3. [1,2,4]Triazolo[1,5- a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration

[1,2,4]Triazolo[1,5- a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration

  • J Med Chem. 2020 Nov 12;63(21):12887-12910. doi: 10.1021/acs.jmedchem.0c01272.
Gary Tresadern 1,  Ingrid Velter 2,  Andrés A Trabanco 3,  Frans Van den Keybus 2,  Gregor J Macdonald 2,  Marijke V F Somers 4,  Greet Vanhoof 4,  Philip M Leonard 5,  Marieke B A C Lamers 5,  Yves E M Van Roosbroeck 2,  Peter J J A Buijnsters 2
Affiliations

Affiliations

  • 1 Computational Chemistry, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 2 Medicinal Chemistry, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 3 Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S. A., Jarama 75A, 45007 Toledo, Spain.
  • 4 Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 5 Structural Biology, Charles River Discovery (Previously BioFocus), Chesterford Research Park, Saffron Walden, CB10 1XL Essex, U.K.
PMID: 33105987 DOI: 10.1021/acs.jmedchem.0c01272
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 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 versus other PDE enzymes, clean Cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.

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