Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists.,Journal of Medicinal Chemistry

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Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-24 , DOI: 10.1021/acs.jmedchem.9b01372
Femke A Meijer ₁ , Richard G Doveston _{1,

2} , Rens M J M de Vries ₁ , Gaël M Vos ₁ , Alex A A Vos ₁ , Seppe Leysen ₁ , Marcel Scheepstra ₁ , Christian Ottmann ₁ , Lech-Gustav Milroy ₁ , Luc Brunsveld ₁

Affiliation

Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly efficient in silico-guided approach that led to the discovery of novel allosteric RORγt inverse agonists with a distinct isoxazole chemotype. The the most potent compound, 25 (FM26), displayed submicromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the RORγt ligand binding domain. The isoxazole compounds have promising pharmacokinetic properties comparable to other allosteric ligands but with a more diverse chemotype. The efficient ligand-based design approach adopted demonstrates its versatility in generating chemical diversity for allosteric targeting of RORγt.

中文翻译：

与配体视黄酸受体相关的孤儿受体γt（RORγt）反向激动剂的基于配体的设计。

视黄酸受体相关的孤儿受体γt（RORγt）是与自身免疫性疾病发病机制相关的核受体。从理论上说，RORγt的变构抑制作用是新的，对于这种特定的核受体而言是独特的，并且比传统的正构抑制作用具有优势。在这里，我们报告了一种高效的计算机模拟方法，该方法导致发现了具有独特异恶唑化学型的新型变构RORγt反向激动剂。最有效的化合物25（FM26）在共激活剂募集试验中显示了亚微摩尔抑制作用，并有效降低了EL4细胞（RORγt活性的标志物）中IL-17a mRNA的产生。通过生化实验和与RORγt配体结合域的共结晶，证实了预计的25种变构作用模式。异恶唑化合物具有与其他变构配体相当的有希望的药代动力学性质，但具有更多样化的化学型。所采用的有效的基于配体的设计方法证明了其在产生化学多样性中用于RORγt的变构靶向的多功能性。

更新日期：2019-12-25

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