Nonalcoholic fatty liver disease (NAFLD) is the build-up of extra fat in liver cells that is not caused by alcohol. It is normal for the liver to contain some fat. However, if more than 5% -10% percent of the liver’s weight is fat, then it is called a fatty liver. The more severe form of NAFLD is called non-alcoholic steatohepatitis (NASH). It may progress to advanced scarring (cirrhosis) and liver failure. NAFLD tends to develop in people when excessive accumulation and deposition of Triacylglycerol (TAG) takes place in hepatocytes and therefore, deregulation of enzymes responsible for controlling intracellular lipid turnover and homeostasis may play an important role in NAFLD. Adipose triglyceride lipase (ATGL) is one such vital enzyme associated with the intracellular degradation of TAG. Constitutive photomorphogenic 1 (COP1) is an E3 ubiquitin ligase that regulates phototropism in plants and targets transcription factors for degradation in mammals. Also, it serves as a crucial regulator in mammalian embryonic development, cellular processes, and the DNA damage response. A recent study suggested that COP1 recognizes and binds with ATGL via the ‘V-P’ motif and degrades it via Ubiquitin Proteasomal System. Thus, targeting COP1 and modulating its activity can help us to increase the proportion of ATGL in hepatic cells which in turn may lower the TAG content in the liver.<br/>In our recent research work, we are aiming to develop a new chemical entity that can behave as a COP1 modulator and thereby can lower the proteasomal degradation of ATGL. Our designed pharmacophore is based on a quinazolinone core with urea linkage to mimic the ‘V-P’ motif of ATGL. The step-by-step SAR modification helped us to understand the role of different substitutions across the quinazolinone core to get better interaction with COP1. Our newly developed quinazolinone compounds can enhance ATGL activities by modifying the COP1 enzyme, according to the encouraging biological data, and they can be employed as a new therapeutic strategy for the treatment of NAFLD.

Hit to lead modification: Design, synthesis, and development of quinazolinone based small molecules for the treatment of non-alcoholic fatty liver disease (NAFLD)

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