Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease and prevalence of NAFLD is reported to be 20%-30% in Western countries and 5%-18% in Asia in absence of significant alcohol consumption, monogenic hereditary disorders, and steatogenic medications. NAFLD is a complex multi-factorial disorder involving the interplay of several molecules and their associated signalling pathways. As is evident, the most prominent feature of NASH is the deposition of excessive Tri-Acyl Glycerol (TAG) in hepatocytes and, therefore, malfunctions in intracellular lipid turnover and homeostasis may play an important role in Non-Alcoholic Fatty Liver Disease. A crucial enzyme responsible for intracellular degradation of TAG is Adipose triglyceride lipase (ATGL) also known as patatin-like phospholipase domain-containing protein 2 (PNPLA2). Constitutive photomorphogenic 1 (COP1), also known as RFWD2, is a E3 ubiquitin ligase serves as a crucial regulator in mammalian embryonic development, cellular processes and the DNA damage response. In recent past, it is established that COP1 predominantly targets hepatic ATGL through ‘V-P’ motif recognition for degradation via Ubiquitin Proteasomal System and knock down of COP1 increases ATGL which in turn lowers the TAG content in liver. Herein, we report the discovery of new chemical entity as COP1 modulator, which could increase the ATGL activity in liver for NAFLD. In our design, the quinazolinone core was substituted at C6 with urea linkage to mimick the ‘V-P’ motif of ATGL, which is important for COP1 recognition. The SAR study revealed strategic substitutions on N3 of quinazolinone core are important for increase in the ATGL concentration. Substitution of the phenyl ring attached to the urea moiety was explored to establish SAR. Our newly designed quinazolinone derivatives have been found to demonstrate improved activities of ATGL by modulating COP1 enzyme and could pave the way for the development of effective NAFLD medications.

Quinazolinone derivatives as COP1 modulator in ameliorating non-alcoholic fatty liver disease

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ACS Fall 2022

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