University of Pittsburgh researchers have synthesized a series of bridged tetrahydroisoquinolines which have been shown to inhibit NADPH Oxidase 2 (Nox2) in a highly selective manner.
Description
Reactive oxygen species (ROS) are involved in the development of numerous diseases and disorders. The family of enzymes, NADPH Oxidases (Nox) are a major source of ROS physiologically through the formation of downstream products, superoxide (O2•-) and/or hydrogen peroxide (H2O2). ROS generation can lead to changes in gene expression, cellular signaling, host defense and inflammation, and cell growth regulation. One member of the Nox family, Nox2, is strongly implicated in cardiovascular disease processes including ischemia, stroke, and hypertension. Selective inhibition of Nox2 could be a novel treatment strategy for these conditions.
Applications
1. Cardiovascular disease
2. Cancer
3. Neurological disorders
4. Other conditions involving ROS
Advantages
To date there have been several pan-Nox inhibitors identified. However, these can bind to numerous isoforms of Nox and not selectively to Nox2. This lack of selectivity is likely to cause undesirable effects given the variety of different isoforms of Nox (and their associated physiological functions) in cells.
These novel compounds have been shown to selectively inhibit only the Nox2 isoform and with IC50 values in micromolar amounts, reduce the risk of side effects in vivo. These small molecules are synthesized in a 2–3 step process from readily available starting materials which would prove beneficial when scaling up production.
Invention Readiness
Using a 2–3 step synthesis, a chemical library of (1SR,4RS)-3,3-Dimethyl-1,2,3,4-tetrahydro-1,4-(epiminomethano)naphthalenes were synthesized from commercially available isoquinolines and assessed for specificity and efficacy across various Nox isoforms. Two compounds, labelled as 11g and 11h, were found to be highly selective Nox2 inhibitors with IC50 values of 20 and 32 mM, respectively. Some therapeutic companies have expressed an interest in this technology.
IP Status
https://patents.google.com/patent/US9796681B2
