Discovery of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway
| Autor: | Simon Peace, Gianpaolo Bravi, Máire A. Convery, Hannah Davies, Graham G. A. Inglis, Joanna M. Redmond, Sandeep Pal, Heather Hobbs, Declan Summers, Ian B. Campbell |
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| Rok vydání: | 2019 |
| Předmět: |
Pyrimidine
Stereochemistry Isostere Morpholines 01 natural sciences mTORC2 Bridged Bicyclo Compounds Phosphatidylinositol 3-Kinases 03 medical and health sciences chemistry.chemical_compound Morpholine Drug Discovery Humans Cycloheptanes PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors 030304 developmental biology 0303 health sciences Hydrogen bond TOR Serine-Threonine Kinases 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Molecular Medicine Pharmacophore Selectivity Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Journal of Medicinal Chemistry. 62:6972-6984 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b00348 |
| Popis: | 4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b). |
| Databáze: | OpenAIRE |
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