A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects
A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects
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DOI：
10.1210/me.2002-0355
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发表时间：
2003-05-01
影响因子：
--
通讯作者：
Miner, JN
中科院分区：
文献类型：
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作者：
Coghlan, MJ;Jacobson, PB;Miner, JN
糖皮质激素（GC）通常用于治疗炎症性疾病；不幸的是，长期使用这些类固醇会导致大量令人衰弱的副作用。 GC 的抗炎作用是 GC 受体 (GR) 介导的促炎基因表达抑制以及 GR 介导的抗炎基因激活的结果。同样，副作用很可能是由于受影响组织中 GR 靶基因的激活和抑制所致。尚未实现的制药目标是开发一种能够将有害副作用与抗炎活性分开的化合物。我们描述了 AL-438 的发现和表征，AL-438 是一种 GR 配体，它表现出改变的基因调控谱，能够抑制和激活通常由 GC 调控的基因的子集。体内测试时，AL-438 保留了与类固醇相当的完整抗炎功效和效力，但在同等抗炎剂量下，其对骨代谢和血糖控制的负面影响减少。这种选择性体外和体内活性的机制可能是响应配体的不同辅因子募集的结果。 AL-438 减少 GR 与过氧化物酶体增殖物激活受体 γ 辅激活剂-1（类固醇介导的葡萄糖上调的关键辅因子）之间的相互作用，同时维持与 GR 相互作用蛋白 1 的正常相互作用。该化合物可作为治疗炎症性疾病中传统 GC 的独特非类固醇替代品的原型。
Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor gamma coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.