Small Inhibitors Targeting Nox4

Background: Fibrosis is the development of excess connective tissue due to the activation ofmyofibroblasts. It is a key process in the pathophysiology of conditions such as lung injuryand kidney disease. Members of the nicotinamide adenine dinucleotide phosphate (NADPH)oxidase (NOX) family catalyze the formation of reactive oxygen species and ROS-formingenzyme, NOX4, and have shown to be a critical mediator of myofibroblast differentiation inlung injury, thereby supporting tissue fibrogenesis. This technology provides a series ofnovel NOX4-specific inhibitors for the therapeutic treatment of IPF and other fibroticdisorders.

Invention: This technology identifies a series of small molecule inhibitors of NOX4 for thetreatment of idiopathic pulmonary fibrosis (IPF)  and other fibrotic disorders. In particular,it provides methods, screening assays, and related absorption, distribution, metabolism,excretion (ADME) studies for the disclosed compounds. This invention explores theimpaired response to cellular oxidative stress as a core pathway to organ fibrosis.

Applications:

·Fulfills the market gap for anti-fibrotic drugs

·An "orphan disease" can be extremely attractive in the strategic development of moving adrug to market

·In addition to all other pharmacochemical properties the IC50 of the lead compounds iscomparable to the GKT NOX1/4 inhibitor in the low to sub micro molar range, implying that these compounds have great potential for clinical translation

Advantages:

·Addresses the unmet need for IPF drug therapies

·This is the first research group to identify NADPH oxidase NOX4 as a mediator ofmyofibroblast activation

·This is the first research group to validate the role of NADPH oxidase NOX4 in animalmodels of lung fibrosis

·Permeability, solubility, and metabolic stability proved favorable for in vitro ADME

·Targets oxidative stress responses in myofibroblasts