Selective inhibition of the iNOS by acetamidine derivatives

Nitric oxide (NO) is a small radical which plays a key role in various physiological as well as pathological processes in mammals, bacteria, and plants. It is produced by enzymatic conversion of the natural substrate _L-Arg, catalyzed by Nitric Oxide Synthases (NOSs), a family of three isoenzymes, including the constitutively expressed neuronal NOS (nNOS) and endothelial NOS (eNOS), and the inducible iNOS. This latter isoform is extensively expressed during inflammation, promoting a sustained generation of NO and reactive nitrogen species, responsible for the damage of a wide variety of biomolecules, including nucleic acids, proteins and lipids.

In the last years, we have designed and synthetized several acetamidines that revealed to be potent and selective inhibitors of both iNOS. Docking studies showed that the acetamidine moiety anchors the inhibitor to the Glu and Trp into the NOS catalytic domain, while other groups extend in the substrate access channel, where are localized the major differences between NOS isoforms. These specific interactions are responsible for the observed activity and selectivity.

In this presentation, the development of two iNOS inhibitors containing the acetamidine moiety will be discussed, starting from the synthesis and evaluation of the inhibitory iNOS activity, up to the description of some biological tests in vitro.