Nitric Oxide: State of the Art in Drug Design

R.A.M.      Serafim; M.C.      Primi; G.H.G.      Trossini; E.I.      Ferreira

doi:10.2174/092986712803414321

Abstract

Since the great discovery of Furchgott, Ignarro and Murad in the late 90's, nitric oxide (NO) is considered one of the most versatile endogenous molecules, which is involved in important signaling biochemistry pathways of the human body. Thus, it is directly related to pathological processes and its over- or low-production is able to cause damage in systems that are involved. By using certain functional groups present in molecules that already have potential therapeutic value, hybrid compounds, by means of inclusion of NO-donors (e.g., ester nitrates, furoxans, benzofuroxans, NONOates, S-nitrosothiols, metal complexes), can be generated that have a NO release benefit along with maintaining the activity of the native drug. This approach has proved to be useful in many spheres of Medicinal Chemistry, such as cardiovascular, inflammatory, bacterial, fungal, viral, parasitic, ocular diseases and cancer. Potent and selective nitric oxide synthase inhibitors are being designed, mainly through enzyme structure based process, however, due to high homology between the isoforms, these studies have proved to be very difficult. The objective of the research is to achieve a balance between the release of therapeutic amounts of NO, especially in specific site of action, and maintaining the native drug activity. The search for new and effective NO-donor hybrid drugs, as well as selective nitric oxide synthase inhibitors, is an important focus in modern drug design in order to manipulate biochemical pathways involving NO that influence many dysfunctions of the human organism.

Keywords: Drug design, nitric oxide, NO-releasing agents, nitric oxide synthase inhibitors, immune system, hybrid compounds, mutual prodrugs, medicinal chemistry, therapeutic potential, biochemical pathways