Feldman P L, Lambert M H, Henke B R
Division of Medicinal Chemistry, Metabolic Diseases Centre of Excellence in Drug Discovery, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Curr Top Med Chem. 2008;8(9):728-49. doi: 10.2174/156802608784535084.
The Peroxisome Proliferator-Activated Receptors-PPAR alpha, PPAR gamma, and PPAR delta--are members of the nuclear receptor gene family that have emerged as therapeutic targets for the development of drugs to treat human metabolic diseases. The discovery of high affinity, subtype-selective agonists for each of the three PPAR subtypes has allowed elucidation of the pharmacology of these receptors and development of first-generation therapeutic agents for the treatment of diabetes and dyslipidemia. However, despite proven therapeutic benefits of selective PPAR agonists, safety concerns and dose-limiting side effects have been observed, and a number of late-stage development failures have been reported. Scientists have continued to explore ligand-based activation of PPARs in hopes of developing safer and more effective drugs. This review highlights recent efforts on two newer approaches, the simultaneous activation of all three PPAR receptors with a single ligand (PPAR pan agonists) and the selective modulation of a single PPAR receptor in a cell or tissue specific manner (selective PPAR modulator or SPPARM) in order to induce a subset of target genes and affect a restricted number of metabolic pathways.
过氧化物酶体增殖物激活受体（PPAR）α、PPARγ和PPARδ是核受体基因家族的成员，已成为开发治疗人类代谢疾病药物的治疗靶点。针对三种PPAR亚型中的每一种发现高亲和力、亚型选择性激动剂，使得能够阐明这些受体的药理学，并开发出用于治疗糖尿病和血脂异常的第一代治疗药物。然而，尽管选择性PPAR激动剂已被证明具有治疗益处，但仍观察到安全问题和剂量限制性副作用，并且已报道了一些后期开发失败的案例。科学家们继续探索基于配体的PPAR激活，希望开发出更安全、更有效的药物。本综述重点介绍了两种较新方法的最新研究成果，即使用单一配体同时激活所有三种PPAR受体（PPAR泛激动剂），以及以细胞或组织特异性方式选择性调节单一PPAR受体（选择性PPAR调节剂或SPPARM），以诱导靶基因的一个子集并影响有限数量的代谢途径。
