2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2010 Jan 1;20(1):375-9. doi: 10.1016/j.bmcl.2009.10.075.
Jeroen C Verheijen 1,  Ker Yu,  Lourdes Toral-Barza,  Irwin Hollander,  Arie Zask
Affiliations

Affiliation

  • 1 Chemical Sciences, Wyeth Research, 401 N. Middletown Rd, Pearl River, NY 10965, USA. [email protected]
PMID: 19897362 DOI: 10.1016/j.bmcl.2009.10.075
Abstract

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) <1nM) mTOR inhibitors with excellent selectivity (up to >1000-fold) over PI3K and good potency in a cellular proliferation assay (IC(50) <50nM).

Figures
Products