Inducible nitric oxide synthase inhibitors: A comprehensive update.

Abstract

Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. l-Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non-amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non-arginine analogs. The latter are further classified into amidines, five- or six-membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors.