Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Pharmacol Res. 2021 Jun;168:105588. doi: 10.1016/j.phrs.2021.105588. Epub 2021 Mar 31.
Glucocorticoids regulate numerous processes in human physiology, but deregulated or excessive glucocorticoid receptor (GR) signaling contributes to the development of various pathologies including metabolic syndrome. For this reason, GR antagonists have considerable therapeutic value. Yet, the only GR antagonist that is clinically approved to date - mifepristone - exhibits cross-reactivity with other nuclear steroid receptors like the progesterone receptor. In this study, we set out to identify novel selective GR antagonists by combining rational chemical design with an unbiased in vitro and in vivo screening approach. Using this pipeline, we were able to identify CORT125329 as the compound with the best overall profile from our octahydro series of novel GR antagonists, and demonstrated that CORT125329 does not exhibit cross-reactivity with the progesterone receptor. Further in vivo testing showed beneficial activities of CORT125329 in models for excessive corticosterone exposure and short- and long-term high-fat diet-induced metabolic complications. Upon CORT125329 treatment, most metabolic parameters that deteriorated upon high-fat diet feeding were similarly improved in male and female mice, confirming activity in both sexes. However, some sexually dimorphic effects were observed including male-specific antagonism of GR activity in brown adipose tissue and female-specific lipid lowering activities after short-term CORT125329 treatment. Remarkably, CORT125329 exhibits beneficial metabolic effects despite its lack of GR antagonism in white adipose tissue. Rather, we propose that CORT125329 treatment restores metabolic activity in brown adipose tissue by stimulating lipolysis, mitochondrial activity and thermogenic capacity. In summary, we have identified CORT125329 as a selective GR antagonist with strong beneficial activities in metabolic disease models, paving the way for further clinical investigation.
糖皮质激素调节人体生理的许多过程，但糖皮质激素受体（GR）信号的失调或过度会导致各种疾病的发展，包括代谢综合征。因此，GR 拮抗剂具有相当大的治疗价值。然而，迄今为止唯一被临床批准的 GR 拮抗剂 - 米非司酮 - 与其他核甾体受体（如孕激素受体）表现出交叉反应。在这项研究中，我们通过将合理的化学设计与无偏的体外和体内筛选方法相结合，旨在确定新型选择性 GR 拮抗剂。使用该流水线，我们能够从我们的新型 GR 拮抗剂八氢系列中鉴定出 CORT125329 作为具有最佳整体特征的化合物，并证明 CORT125329 与孕激素受体没有交叉反应。进一步的体内测试表明，CORT125329 在皮质酮暴露过度和短期和长期高脂肪饮食诱导的代谢并发症模型中具有有益的活性。在 CORT125329 治疗后，高脂肪饮食喂养导致的大多数代谢参数都得到了类似的改善，证实了雌雄两性都有活性。然而，观察到一些性别二态性效应，包括雄性特异性拮抗棕色脂肪组织中的 GR 活性和短期 CORT125329 治疗后的雌性特异性脂质降低活性。值得注意的是，尽管 CORT125329 缺乏对白色脂肪组织中的 GR 拮抗作用，但它仍表现出有益的代谢作用。相反，我们提出 CORT125329 通过刺激脂肪分解、线粒体活性和产热能力来恢复棕色脂肪组织的代谢活性。总之，我们已经确定 CORT125329 是一种具有强大代谢疾病模型治疗活性的选择性 GR 拮抗剂，为进一步的临床研究铺平了道路。
