Monoacylglycerol transferase 2 (MGAT2) is a pivotal enzyme in the monoacylglycerol pathway for triacylglycerol synthesis. The pathway for triacylglycerol synthesis has provided several attractive targets for drug discovery in the treatment of metabolic diseases. Marketed drugs that inhibit enzymes in this pathway include orlistat (pancreatic lipase inhibitor), lomitapide (mitochondrial transfer protein inhibitor), and mipomersen (apolipoprotein B synthesis inhibitor), but poor gastrointestinal (GI) tolerability or safety considerations have limited their use and indications. In addition, several inhibitors of diacylglycerol transferase 1 (DGAT1) have advanced to the clinic but were withdrawn due to poor GI tolerability. This report first discusses the biological rationale in support of inhibition of MGAT2 as a therapeutic approach that may offer a distinct and superior efficacy versus GI tolerability profile and then reviews advances in the discovery of small molecule MGAT2 inhibitors for the treatment of metabolic diseases and nonalcoholic steatohepatitis (NASH).

中文翻译：

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单酰基甘油酰基转移酶2（MGAT2）抑制剂，用于治疗代谢性疾病和非酒精性脂肪性肝炎（NASH）

单酰基甘油转移酶2（MGAT2）是单酰基甘油途径中三酰基甘油合成的关键酶。三酰基甘油合成的途径为治疗代谢性疾病的药物发现提供了几个有吸引力的目标。抑制该途径中酶的市售药物包括orlistat（胰腺脂肪酶抑制剂），lomitapide（线粒体转移蛋白抑制剂）和mipomersen（载脂蛋白B合成抑制剂），但胃肠道（GI）耐受性差或安全性考虑因素限制了它们的使用和适应症。此外，一些二酰基甘油转移酶1（DGAT1）抑制剂已进入临床，但由于胃肠道耐受性差而被撤回。