2. Academic Validation
  3. Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent

Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent

  • Bioorg Med Chem Lett. 2010 Feb 15;20(4):1440-4. doi: 10.1016/j.bmcl.2009.12.086.
Kevin J Curran 1,  Jeroen C Verheijen,  Joshua Kaplan,  David J Richard,  Lourdes Toral-Barza,  Irwin Hollander,  Judy Lucas,  Semiramis Ayral-Kaloustian,  Ker Yu,  Arie Zask
Affiliations

Affiliation

  • 1 Chemical Sciences, Wyeth Research, 401 N. Middletown Rd, Pearl River, NY 10965, USA. [email protected]
PMID: 20089401 DOI: 10.1016/j.bmcl.2009.12.086
Abstract

A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8h following iv administration and showed excellent oral activity in a xenograft tumor model.

Figures