Wiesenberg I, Chiesi M, Missbach M, Spanka C, Pignat W, Carlberg C
Pharma Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
Mol Pharmacol. 1998 Jun;53(6):1131-8.
The thiazolidinedione BRL 49653 and the thiazolidinedione derivative CGP 52608 are lead compounds of two pharmacologically different classes of compounds. BRL 49653 is a high affinity ligand of peroxisome proliferator-activated receptor gamma (PPARgamma) and a prototype of novel antidiabetic agents, whereas CGP 52608 activates retinoic acid receptor-related orphan receptor alpha (RORA) and exhibits potent antiarthritic activity. Both receptors belong to the superfamily of nuclear receptors and are structurally related transcription factors. We tested BRL 49653 and CGP 52608 for receptor specificity on PPARgamma, RORA, and retinoic acid receptor alpha, a closely related receptor to RORA, and compared their pharmacological properties in in vitro and in vivo models in which these compounds have shown typical effects. BRL 49653 specifically induced PPARgamma-mediated gene activation, whereas CGP 52608 specifically activated RORA in transiently transfected cells. Both compounds were active in nanomolar concentrations. Leptin production in differentiated adipocytes was inhibited by nanomolar concentrations of BRL 49653 but not by CGP 52608. BRL 49653 antagonized weight loss, elevated blood glucose levels, and elevated plasma triglyceride levels in an in vivo model of glucocorticoid-induced insulin resistance in rats, whereas CGP 52608 exhibited steroid-like effects on triglyceride levels and body weight in this model. In contrast, potent antiarthritic activity in rat adjuvant arthritis was shown for CGP 52608, whereas BRL 49653 was nearly inactive. Our results support the concept that transcriptional control mechanisms via the nuclear receptors PPARgamma and RORA are responsible at least in part for the different pharmacological properties of BRL 49653 and CGP 52608. Both compounds are prototypes of interesting novel therapeutic agents for the treatment of non-insulin-dependent diabetes mellitus and rheumatoid arthritis.
噻唑烷二酮类化合物BRL 49653和噻唑烷二酮衍生物CGP 52608是两类药理性质不同的化合物的先导化合物。BRL 49653是过氧化物酶体增殖物激活受体γ（PPARγ）的高亲和力配体，是新型抗糖尿病药物的原型，而CGP 52608激活视黄酸受体相关孤儿受体α（RORA）并表现出强效的抗关节炎活性。这两种受体都属于核受体超家族，是结构相关的转录因子。我们测试了BRL 49653和CGP 52608对PPARγ、RORA以及视黄酸受体α（与RORA密切相关的受体）的受体特异性，并在体外和体内模型中比较了它们的药理特性，在这些模型中这些化合物已显示出典型作用。BRL 49653特异性诱导PPARγ介导的基因激活，而CGP 52608在瞬时转染细胞中特异性激活RORA。两种化合物在纳摩尔浓度下均有活性。纳摩尔浓度的BRL 49653可抑制分化脂肪细胞中瘦素的产生，但CGP 52608则不能。在大鼠糖皮质激素诱导的胰岛素抵抗体内模型中，BRL 49653拮抗体重减轻、血糖水平升高和血浆甘油三酯水平升高，而在该模型中CGP 52608对甘油三酯水平和体重表现出类甾体样作用。相反，CGP 52608在大鼠佐剂性关节炎中显示出强效的抗关节炎活性，而BRL 49653几乎没有活性。我们的结果支持这样一种观点，即通过核受体PPARγ和RORA的转录控制机制至少部分地导致了BRL 49653和CGP 52608不同的药理特性。这两种化合物都是用于治疗非胰岛素依赖型糖尿病和类风湿性关节炎的有趣新型治疗药物的原型。
