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Beschreibung

A cell-permeable biphenyldimethyl urea compound that inhibits adipose triglyceride lipase (ATGL) activity (IC50 = 700 nM, [Substrate] = [Triolein] = 165 µ,M) in a substrate-competitive (Ki = 355 nM) and highly selective manner, exhibiting little potency against hormone-sensitive lipase (HSL), monoglyceride lipase (MGL), pancreatic lipase, lipoprotein lipase, or lysophospholipases PNPLA6/7 even at concentrations as high as 100 µ,M. Shown to effectively suppress FA/glycerol productions from adipocytes (ICmax = 50 to 100 µ,M in 3T3-L1-differentiated adipocytes or primary murine white adipose tissue/WAT cultures) in vitro and in blood of mice in vivo via either oral or intraperitoneal administration (EDmax = 200 µ,mol/kg) without affecting plasma glucose, total cholesterol, insulin, or beta-hydroxybutyrate (beta-HB) level. Significant cytotoxicity is reported at concentrations >50 µ,M in AML-12 murine hepatocyte cultures. Although ATGL deficiency causes cardiomyopathy in human and ATGL-ko animals due to severe triacylglycerol (TG) accumulation in cardiac muscle, significant atglistatin level (>0.2 nmol/g tissue) is only seen in liver, white and brown adipose tissues, and detectable TG accumulation is only observed in liver tissue in wt mice 8 h post single 200 µ,mol/kg oral dosage.