Synthesis and Stability of Oxetane Analogs of Thalidomide and Lenalidomide

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.