| Autor: |
Tresadern G; Computational Chemistry, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Velter I; Medicinal Chemistry, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Trabanco AA; Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S. A., Jarama 75A, 45007 Toledo, Spain., Van den Keybus F; Medicinal Chemistry, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Macdonald GJ; Medicinal Chemistry, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Somers MVF; Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Vanhoof G; Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Leonard PM; Structural Biology, Charles River Discovery (Previously BioFocus), Chesterford Research Park, Saffron Walden, CB10 1XL Essex, U.K., Lamers MBAC; Structural Biology, Charles River Discovery (Previously BioFocus), Chesterford Research Park, Saffron Walden, CB10 1XL Essex, U.K., Van Roosbroeck YEM; Medicinal Chemistry, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium., Buijnsters PJJA; Medicinal Chemistry, Janssen Pharmaceutica N. V., Turnhoutseweg 30, B-2340 Beerse, Belgium. |
| Abstrakt: |
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 50 's from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC 50 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. |
