149108-74-7Relevant articles and documents
Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration
Tresadern, Gary,Velter, Ingrid,Trabanco, Andrés 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.
, p. 12887 - 12910 (2020/11/13)
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, a 100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.
TRISUBSTITUTED PYRIMIDINE COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF CANCER, RETINAL DISORDERS, AND CARDIOMYOPATHIES
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Page/Page column 35; 36, (2018/11/26)
The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof: It further discloses a pharmaceutical composition comprising the compounds of Formula (I) and their uses, in particular in the treatment of
Aminoheteroaryl benzamides as kinase inhibitors
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Page/Page column 385; 388, (2016/02/15)
The present invention provides a compound of Formula (I) or a salt thereof; and therapeutic uses of these compounds. The present invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds with a therapeutic co-agent.
