Synthesis and stability of oxetane analogs of thalidomide and lenalidomide

Org Lett. 2013 Sep 6;15(17):4312-5. doi: 10.1021/ol401705a. Epub 2013 Aug 12.


Oxetanes are used in drug discovery to enable physicochemical and metabolic property enhancement for the structures to which they are grafted. An imide C═O to oxetane swap on thalidomide and lenalidomide templates provides analogs with similar physicochemical and in vitro properties of the parent drugs, with an important exception: oxetane analog 2 displays a clear differentiation with respect to human plasma stability. The prospect of limiting in vivo stability/metabolism, blocking in vivo racemization, and potentially altering teratogenicity is appealing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Discovery
  • Ethers, Cyclic / blood
  • Ethers, Cyclic / chemical synthesis*
  • Ethers, Cyclic / chemistry
  • Hepatocytes / metabolism
  • Humans
  • Lenalidomide
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Rats
  • Thalidomide / analogs & derivatives*
  • Thalidomide / blood
  • Thalidomide / chemical synthesis*
  • Thalidomide / chemistry


  • Ethers, Cyclic
  • Thalidomide
  • Lenalidomide
  • oxetane