Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion,ACS Medicinal Chemistry Letters

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Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-09-15 , DOI: 10.1021/acsmedchemlett.1c00379
Brandon J Kennedy ₁ , Ashley M Lato ₁ , Alexander R Fisch ₁ , Susan J Burke ₂ , Justin K Kirkland ₁ , Carson W Prevatte ₁ , Lee E Dunlap ₁ , Russell T Smith ₁ , Konstantinos D Vogiatzis ₁ , J Jason Collier ₂ , Shawn R Campagna ₁

Affiliation

Glucocorticoids (GCs) are widely used in medicine for their role in the treatment of autoimmune-mediated conditions, certain cancers, and organ transplantation. The transcriptional activities GCs elicit include transrepression, postulated to be responsible for the anti-inflammatory activity, and transactivation, proposed to underlie the undesirable side effects associated with long-term use. A GC analogue that could elicit only transrepression and beneficial transactivation properties would be of great medicinal value and is highly sought after. In this study, a series of 1-(4-substituted phenyl)pyrazole-based GC analogues were synthesized, biologically screened, and evaluated for SARs leading to the desired activity. Activity observed in compounds bearing an electron deficient arylpyrazole moiety showed promise toward a dissociated steroid, displaying transrepression while having limited transactivation activity. In addition, compounds 11aa and 11ab were found to have anti-inflammatory efficacy comparable to that of dexamethasone at 10 nM, with minimal transactivation activity and no reduction of insulin secretion in cultured rat 832/13 beta cells.

中文翻译：

不损害胰岛素分泌的强效抗炎、芳基吡唑基糖皮质激素受体激动剂

糖皮质激素 (GC) 因其在治疗自身免疫介导疾病、某些癌症和器官移植中的作用而广泛用于医学。GCs 引发的转录活动包括反式阻抑（假定负责抗炎活性）和反式激活（被认为是与长期使用相关的不良副作用的基础）。只能引起反式抑制和有益的反式激活特性的 GC 类似物将具有巨大的药用价值并受到高度追捧。在本研究中，合成了一系列基于 1-(4-取代苯基)吡唑的 GC 类似物，对其进行了生物学筛选，并评估了 SAR 的相关活性。在带有缺电子芳基吡唑部分的化合物中观察到的活性显示出对解离类固醇的希望，显示反式抑制，同时具有有限的反式激活活动。此外，化合物发现11aa和11ab在 10 nM 时具有与地塞米松相当的抗炎功效，在培养的大鼠 832/13 β 细胞中具有最小的反式激活活性并且没有减少胰岛素分泌。

更新日期：2021-10-14

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