1009622-45-0Relevant academic research and scientific papers
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
Hobbs, Heather,Bravi, Gianpaolo,Campbell, Ian,Convery, Maire,Davies, Hannah,Inglis, Graham,Pal, Sandeep,Peace, Simon,Redmond, Joanna,Summers, Declan
supporting information, p. 6972 - 6984 (2019/09/16)
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).
Discovery of AZD3147: A potent, selective dual inhibitor of mTORC1 and mTORC2
Pike, Kurt G.,Morris, Jeff,Ruston, Linette,Pass, Sarah L.,Greenwood, Ryan,Williams, Emma J.,Demeritt, Julie,Culshaw, Janet D.,Gill, Kristy,Pass, Martin,Finlay, M. Raymond V.,Good, Catherine J.,Roberts, Craig A.,Currie, Gordon S.,Blades, Kevin,Eden, Jonathan M.,Pearson, Stuart E.
, p. 2326 - 2349 (2015/03/30)
High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.
