Application

Quinazolin-4(3H)-one derivatives as selective NOX-2 inhibitors to prevent oxidative damage.

Key Benefits

• Small molecule NOX-2 specific inhibitor.
• Prevents excessive reactive oxygen species (ROS) generation rather than removing them.
• Selective NOX-2 inhibition offers significant advantages to development of an effective therapy against acute lung injury, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and pulmonary hypertension, as well as CNS diseases and inflammatory diseases.

Market Summary

Oxidative stress is essential to many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer's disease, and cancer. NADPH oxidases (NOX) activation results in reactive oxygen species (ROS) production and associated oxidative stress, which exacerbates secondary pathologies of a multitude of diseases. Although numerous medicines have been developed and evaluated as antioxidants with promising therapeutic potential in preclinical studies, clinical trial results have been disappointing. Hence, creating safe and efficacious drugs that block the underlying molecular mechanism of oxidative stress can potentially treat a plethora of diseases.

Technical Summary

Researchers at Emory with quinazolinone derivatives developed a novel quinazolin-4(3H)-one derivates as selective NOX-2 inhibitors: TG15-132S, TG15-139S, TG17-57, and LY4-123S. All of these compounds showed NOX-2 specific inhibitory activities without any noticeable indication of ROS scavenging. Preliminary in vivo pharmacokinetics assays suggests that TG15-132S already has drug-like activity profile with an excellent clearance rate with an appreciable half-life in plasma and brain (with brain-to-plasma ration greater than 10). These results present TG15-132S as an attractive preclinical and clinical therapeutics candidate. Further studies in human leukemia monocytic cell line where overexpression of NOX-2 is induced showed significant reduction in mRNA levels of IL-1β and TNF demonstrating TG15-132S’ anti-inflammatory activities. Such finding offers a promising approach to the development of an effective therapeutics against inflammatory dieses and respiratory diseases including ARDS caused by SARS-CoV-2 virus infection.

Developmental Stage

Preclinical, in vitro proof of concept demonstrating the compound’s specificity to NOX-2, in vivo (rat) pharmacokinetic study.