Quinazolin-4(3H)-one Derivatives as NOX-2 Inhibitors: Composition of Matter, Methods of Preparation and Their Use

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
NOX2 is expressed in high levels especially in phagocytic cells and its activity is connected to reactive oxygen species (ROS) generation, so the current invention is related to therapeutics for the inflammatory disease market. The global market for enzyme inhibitors is expected to reach $179.9 billion in 2022 from $168 billion in 2017 (BCC Research: BIO057C). Furthermore, the anti-inflammatory therapeutics market is expected to reach $130.6 billion by 2026 with a CAGR of 8.5% from 2018-2026. Currently, there are no marketed NOX-2 inhibitors or any NOX isoform specific inhibitor.

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

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