Discovery and Development of Quinazolinones and Quinazolinediones for Ameliorating Nonalcoholic Fatty Liver Disease (NAFLD) by Modulating COP1-ATGL Axis.

Abstract

E3 ubiquitin ligase, Constitutive Photomorphogenic 1 (COP1) regulates turnover of Adipose Triglyceride Lipase (ATGL), the rate-limiting lipolytic enzyme. Genetic perturbation in the COP1-ATGL axis disrupts lipid homeostasis, leading to liver steatosis. Using drug development strategies, we herein report quinazolinone and quinazolinedione based modulators for COP1-ATGL axis. Systematic SAR studies and subsequent optimization were performed by incorporating relevant functional groups at the N1, N3, C5, and C6 positions of both scaffolds. Compounds' efficacy was evaluated by multiple biological assays and ADME profiling. The lead compound 86 could increase ATGL protein expression, reduce ATGL ubiquitination and COP1 autoubiquitination, and diminish lipid accumulation in hepatocytes in the nanomolar range. Oral administration of 86 abrogated triglyceride accumulation and resolved fibrosis in preclinical Nonalcoholic Fatty Liver Disease (NAFLD) model. The study thus establishes quinazolinedione as a viable chemotype to therapeutically modulate the activity of COP1 and ATGL in relevant clinical contexts.