大环维甲酸受体相关孤儿受体C2反向激动剂
Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists.
作者信息
Schnute Mark E, Trujillo John I, Lee Katherine L, Unwalla Ray, Vajdos Felix F, Kauppi Björn, Nuhant Philippe, Flick Andrew C, Crouse Kimberly K, Zhao Yajuan, Samuel Amanda, Lombardo Vincent, Taylor Alexandria P, Brault Amy L, Knafels John D, Vazquez Michael L, Berstein Gabriel
机构信息
Medicine Design, Pfizer Inc., Cambridge, Massachusetts 02139, United States.
Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States.
出版信息
ACS Med Chem Lett. 2023 Jan 18;14(2):191-198. doi: 10.1021/acsmedchemlett.2c00500. eCollection 2023 Feb 9.
Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.
大环维甲酸受体相关孤儿受体C2（RORC2）反向激动剂已被设计成具有适合局部给药的良好特性。通过共晶体结构分析，受一种基于无环磺酰胺的RORC2配体意外的结合构象启发，对分子两半之间的大环连接体连接进行了探索。通过对类似物的进一步优化，以最大化效力并改善最适合局部应用的理化性质（分子量、亲脂性）。化合物表现出对人Th17细胞产生白细胞介素-17A（IL-17A）的强效抑制作用，并在体外透过健康人皮肤，在皮肤表皮和真皮层均达到较高的化合物总浓度。
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