Department Cardiovascular and Diabetes Discovery, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
J Med Chem. 2013 Dec 27;56(24):9820-5. doi: 10.1021/jm4007033. Epub 2013 Sep 3.
Diacylglycerol O-acyltransferase 1 (DGAT1) has recently become a highly interesting target for metabolic disorders as well as for hepatitis C virus (HCV). DGAT1 processes diacylglycerol to triglycerides in the final step of resynthesis for the absorption of fat across the intestine. Pharmaceutical companies have developed many novel inhibitors of DGAT1, several of which have reached the clinic. Proof of target engagement was achieved with the observation of reduced triglycerides upon treatment of humans with DGAT1 inhibitors; however, there were gastrointestinal adverse events such as nausea, diarrhea, and vomiting. These adverse events have been reported with multiple compounds and are possibly linked to the target because of the recent identification of a human cohort deficient in DGAT1. Clinical studies are continuing in a trial to treat patients with an orphan indication for familial chylomicronemia. The full potential of DGAT1 as a therapeutic target will need to overcome observed clinical adverse events, which are possibly mechanism based. The widespread use of DGAT1 inhibitors will ultimately depend upon a better understanding of how to improve the GI tolerability of these agents.
二酰基甘油酰基转移酶 1（DGAT1）最近成为代谢紊乱以及丙型肝炎病毒（HCV）的一个非常有吸引力的靶标。DGAT1 在肠内吸收脂肪的重新合成的最后一步中将二酰基甘油加工成三酰基甘油。制药公司已经开发了许多 DGAT1 的新型抑制剂，其中有几种已经进入临床阶段。用 DGAT1 抑制剂治疗人类时观察到甘油三酯减少，从而证明了靶标结合；然而，有胃肠道不良反应，如恶心、腹泻和呕吐。由于最近发现 DGAT1 缺乏的人类队列，因此已经报道了这些不良反应，并且由于最近发现了 DGAT1 缺乏的人类队列，这些不良反应可能与该靶标有关。正在进行一项临床试验，以治疗患有家族性乳糜微粒血症孤儿症的患者。要充分发挥 DGAT1 作为治疗靶标的潜力，需要克服观察到的可能基于机制的临床不良反应。DGAT1 抑制剂的广泛使用最终将取决于更好地了解如何提高这些药物的胃肠道耐受性。
