Reversible Michael Additions: Covalent Inhibitors and Prodrugs

Martin      H. Johansson

doi:10.2174/13895575112091330

Abstract

Covalent inhibition is an efficient molecular mechanism for inhibiting enzymes or modulating the function of proteins and is found in the action of many drugs and biologically active natural products. However, it is has been less appreciated that the formation of covalent bonds can be reversible or irreversible. This review focuses on biologically active compounds that are Michael acceptors and how the reversible nature of the Michael addition reaction influences biological activity and how this can be exploited in designing prodrugs.

Keywords: Covalent inhibition, Michael addition, natural products, prodrug, reversible, polypharmacology, CNS drugs, 3-aminopropanamides, non-covalent, β-unsaturated