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.
Laboratorium für Organische Chemie, ETH Zürich, CH-8093 Zürich, Switzerland.
Johannes A
JA
Burkhard
Georg
G
Wuitschik
Jean-Marc
JM
Plancher
Mark
M
Rogers-Evans
Erick M
EM
Carreira
D000818:Animals; D055808:Drug Discovery; D004988:Ethers, Cyclic / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D000077269:Lenalidomide; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry
D004988:Ethers, Cyclic; D013792:Thalidomide; D000077269:Lenalidomide; C005287:oxetane