Discovery of 2-arylthieno[3,2- d]pyrimidines containing 8-oxa-3-azabi-cyclo[3.2.1]octane in the 4-position as potent inhibitors of mTOR with selectivity over PI3K

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 1; pp. 375 - 379
• Main Authors: Verheijen, Jeroen C., Yu, Ker, Toral-Barza, Lourdes, Hollander, Irwin, Zask, Arie
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 2010
• Subjects: Cancer; Cell Line, Tumor; Drug Discovery; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Kinase; Morpholines - chemistry; mTOR; Oncology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; PI3K; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tropanes - chemistry; mTOR; Oncology; PI3K; Kinase; Cancer
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.10.075

Introduction of bridged morpholine and ureidophenyl on moderately potent thienopyrimidine dual PI3K/mTOR inhibitors led to excellent mTOR potency and selectivity over PI3K. 2-Aryl-4-morpholinothieno[3,2- d]pyrimidines are known PI3K inhibitors. This class of compounds also potently inhibited the homologous enzyme mTOR. Replacement of the morpholine group in these compounds with an 8-oxa-3-azabicyclo[3.2.1]octane group led to mTOR inhibitors with selectivity over PI3K. Optimization of the 2-aryl substituent led to the discovery of 2-(4-ureidophenyl)-thienopyrimidines as highly potent (IC 50 <1 nM) mTOR inhibitors with excellent selectivity (up to >1000-fold) over PI3K and good potency in a cellular proliferation assay (IC 50 <50 nM).