Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Future Med Chem. 2011 Dec;3(16):2039-61. doi: 10.4155/fmc.11.158.
Acyl-CoA:cholesterol acyltransferase (ACAT) is a promising therapeutic target for cardiovascular diseases. Although a number of synthetic ACAT inhibitors have been developed, they have failed to show efficacy in clinical trials. Now, the presence of two ACAT isoforms with distinct functions, ACAT1 and ACAT2, has been discovered. Thus, the selectivity of ACAT inhibitors toward the two isoforms is important for their development as novel anti-atherosclerotic agents. The selectivity study indicated that fungal pyripyropene A (PPPA) is only an ACAT2-specific inhibitor. Furthermore, PPPA proved orally active in atherogenic mouse models, indicating it possessed cholesterol-lowering and atheroprotective activities. Certain PPPA derivatives, semi-synthetically prepared, possessed more potent and selective in vitro activity than PPPA against ACAT2. This review covers these studies and describes the future prospects of ACAT2-specific inhibitors.
酰基辅酶 A：胆固醇酰基转移酶（ACAT）是心血管疾病有前途的治疗靶点。尽管已经开发了许多合成的 ACAT 抑制剂，但它们在临床试验中未能显示出疗效。现在，已经发现了两种具有不同功能的 ACAT 同工酶，即 ACAT1 和 ACAT2。因此，ACAT 抑制剂对两种同工酶的选择性对于将其开发为新型抗动脉粥样硬化药物很重要。选择性研究表明，真菌吡嗪并吡喃 A（PPPA）仅是 ACAT2 的特异性抑制剂。此外，PPPA 在动脉粥样硬化的小鼠模型中被证明具有口服活性，表明其具有降低胆固醇和抗动脉粥样硬化作用。某些半合成制备的 PPPA 衍生物对 ACAT2 的体外活性比 PPPA 更强且更具选择性。本综述涵盖了这些研究，并描述了 ACAT2 特异性抑制剂的未来前景。
