The first generation of Nitric Oxide Synthases inhibitors was synthesized in the late 1980’s
and early 1990’s; they were mainly amino acid derivatives, binding to the same residues within the
enzyme heme-active site with respect to the natural substrate L-Arg, and showed no or scarce selectivity.
In 1994, the N-(3-(aminomethyl)-benzyl) acetamidine (1400W), a highly selective compound for
human iNOS versus both human eNOS and nNOS, was discovered. Following this landmark discover
several other amidine-based iNOS and nNOS selective inhibitors have been disclosed. In this review
we will focus on the recent progress and perspectives in the development of amidine-based selective
iNOS and nNOS, including close analogues, with particular attention to acetamidine and aminopyridine