Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
Expert Opin Ther Pat. 2010 Jan;20(1):19-29. doi: 10.1517/13543770903499305.
Postprandial hypertriglyceridemia has been identified as a major independent risk factor for future cardiovascular events. Therefore, inhibition of triglyceride synthesis has enormous therapeutic potential in the treatment of metabolic disorders. Diacylglycerol acyltransferase (DGAT) enzymes catalyze the final and only committed step in triglyceride biosynthesis and have thus been identified as potential therapeutic targets to combat human cardio-metabolic diseases.
OBJECTIVE/METHOD: Significant interest in DGAT-1 inhibitors has emerged in the last several years. To provide a perspective on the exciting features of this enzyme for targeting metabolic diseases, a summary of the biology and pharmacology surrounding the DGAT enzymes is presented. Following this is a discussion of the various chemotypes that have been disclosed within relevant patent applications published in 2008. Specifically, the similarities and differences of the chemical structures and the biological data that are provided to support the corresponding claims are presented.
Small molecule and biologic-based DGAT inhibitors have been successfully used for the preclinical validation of DGAT enzymes as targets for the treatment of metabolic diseases. Given the advanced stage in which some of the chemical matter resides, it is expected that DGAT inhibitors will enter the clinic in the coming years.
餐后高甘油三酯血症已被确定为未来心血管事件的一个主要独立危险因素。因此，抑制甘油三酯合成在治疗代谢紊乱方面具有巨大的治疗潜力。二酰基甘油酰基转移酶（DGAT）酶催化甘油三酯生物合成的最后也是唯一的关键步骤，因此已被确定为治疗人类心脏代谢疾病的潜在治疗靶点。
目的/方法：近年来，人们对 DGAT-1 抑制剂产生了浓厚的兴趣。为了从靶向代谢疾病的角度了解该酶的令人兴奋的特征，本文对 DGAT 酶的生物学和药理学进行了总结。接下来讨论了在 2008 年公布的相关专利申请中公开的各种化学类型。具体来说，本文提供了支持相应权利要求的化学结构和生物学数据的相似性和差异。
小分子和基于生物的 DGAT 抑制剂已成功用于 DGAT 酶作为治疗代谢疾病的靶点的临床前验证。鉴于一些化学物质所处的先进阶段，预计 DGAT 抑制剂将在未来几年进入临床。
