Merging Natural Product Structures with Pharmaceutical Leads: Unnatural Enantiomers of Estranes as Glucocorticoid Receptor Modulators That Suppress TNF-α and IL-6 Release,Journal of Medicinal Chemistry

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Merging Natural Product Structures with Pharmaceutical Leads: Unnatural Enantiomers of Estranes as Glucocorticoid Receptor Modulators That Suppress TNF-α and IL-6 Release
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-06 , DOI: 10.1021/acs.jmedchem.4c01007
Joshua M Nicholson ₁ , Dexi Yang ₂ , Thomas Koelblen ₃ , Eric L Hu ₄ , Christopher C Coss ₅ , Thomas P Burris ₃ , Xiao Hu ₆ , Glenn C Micalizio ₁

Affiliation

Natural products are widely recognized as valuable starting points for the development of therapeutics, with synthetic tetracyclic triterpenoids (e.g., steroids) being the most well represented among the drugs approved by the Food and Drug Administration. Here, recently developed synthetic tools for concise, asymmetric, and convergent construction of steroidal systems are leveraged to drive a program aimed at identifying novel glucocorticoid receptor (GR) modulators. While glucocorticoids have been extensively used as anti-inflammatory agents, they are plagued by severe side effects that include bone loss, muscle wasting, and metabolic disease. Ultimately, a program targeting the unnatural enantiomers of estranes (ent-estranes) that are practically inaccessible from natural product derivatization (semisynthesis) has resulted in the identification of a new class of potent dissociated GR modulators. We identify several leads with >99% efficacy as antagonists of GR trans-activation (potency within 10-fold of that of mifepristone) and further characterize examples that also inhibit release of pro-inflammatory cytokines IL-6 and TNF-α.

中文翻译：

将天然产物结构与药物线索相结合：雌纤烷的非天然对映异构体作为抑制 TNF-α 和 IL-6 释放的糖皮质激素受体调节剂

天然产物被广泛认为是开发治疗方法的宝贵起点，其中合成的四环三萜类化合物（例如类固醇）是美国食品药品监督管理局批准的药物中代表性最强的药物。在这里，利用最近开发的用于简洁、不对称和收敛构建类固醇系统的合成工具来推动一项旨在识别新型糖皮质激素受体（GR）调节剂的计划。虽然糖皮质激素已被广泛用作抗炎剂，但它们受到严重副作用的困扰，包括骨质流失、肌肉萎缩和代谢疾病。最终，一个针对几乎无法从天然产物衍生化（半合成）中获得的雌雄雌异构体（ent-estranes）的非天然对映异构体的程序导致了一类新型有效的解离 GR 调节剂的鉴定。我们确定了几种具有 >99% 功效的线索作为 GR 反式激活的拮抗剂（效力在米非司酮的 10 倍以内），并进一步表征了也抑制促炎细胞因子 IL-6 和 TNF-α 释放的例子。

更新日期：2024-09-06

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