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本文引用的文献

1
Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist.BMS-986251的发现：一种具有临床可行性、强效且选择性的RORγt反向激动剂。
ACS Med Chem Lett. 2020 Mar 31;11(6):1221-1227. doi: 10.1021/acsmedchemlett.0c00063. eCollection 2020 Jun 11.
2
New Perspectives on Drug-Induced Liver Injury Risk Assessment of Acyl Glucuronides.酰基葡萄糖醛酸化物药物性肝损伤风险评估的新视角。
Chem Res Toxicol. 2020 Jul 20;33(7):1551-1560. doi: 10.1021/acs.chemrestox.0c00131. Epub 2020 Jun 29.
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Rationally Designed, Conformationally Constrained Inverse Agonists of RORγt-Identification of a Potent, Selective Series with Biologic-Like in Vivo Efficacy.理性设计、构象约束的 RORγt 反向激动剂——具有体内生物学疗效的高效、选择性系列化合物的鉴定。
J Med Chem. 2019 Nov 14;62(21):9931-9946. doi: 10.1021/acs.jmedchem.9b01369. Epub 2019 Oct 31.
4
Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORγt Inverse Agonists.基于结构发现苯基（3-苯基吡咯烷-3-基）砜类化合物作为选择性、口服活性RORγt反向激动剂
ACS Med Chem Lett. 2019 Feb 26;10(3):367-373. doi: 10.1021/acsmedchemlett.9b00010. eCollection 2019 Mar 14.
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Applications of Deuterium in Medicinal Chemistry.氘在药物化学中的应用。
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Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ or RORc) Inhibitors: Hits and Misses.用维甲酸相关孤儿受体-γ（RORγ 或 RORc）抑制剂治疗自身免疫性疾病：成功与失败。
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Retinoic Acid-Related Orphan Receptors (RORs): Regulatory Functions in Immunity, Development, Circadian Rhythm, and Metabolism.维甲酸相关孤儿受体（RORs）：在免疫、发育、昼夜节律和代谢中的调节功能
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使用虚拟筛选方法鉴定出的新型三环焦谷氨酰胺衍生物作为有效的RORγt反向激动剂。

Novel Tricyclic Pyroglutamide Derivatives as Potent RORγt Inverse Agonists Identified using a Virtual Screening Approach.

作者信息

Liu Qingjie, Batt Douglas G, Weigelt Carolyn A, Yip Shiuhang, Wu Dauh-Rurng, Ruzanov Max, Sack John S, Wang Jinhong, Yarde Melissa, Li Sha, Shuster David J, Xie Jenny H, Sherry Tara, Obermeier Mary T, Fura Aberra, Stefanski Kevin, Cornelius Georgia, Khandelwal Purnima, Tino Joseph A, Macor John E, Salter-Cid Luisa, Denton Rex, Zhao Qihong, Dhar T G Murali

机构信息

Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.

出版信息

ACS Med Chem Lett. 2020 Nov 6;11(12):2510-2518. doi: 10.1021/acsmedchemlett.0c00496. eCollection 2020 Dec 10.

DOI:10.1021/acsmedchemlett.0c00496
PMID:33335675
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7734821/
Abstract

Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure-activity relationship optimization of the pyroglutamide moiety led to the identification of compound as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis.

摘要

采用虚拟筛选方法，我们确定焦谷氨酰胺部分可作为环己烷羧酸基团的非酸性替代物，当与我们先前报道的构象锁定三环核心偶联时，可提供强效且选择性的RORγt反向激动剂。对焦谷氨酰胺部分进行构效关系优化后，确定化合物为强效且选择性的RORγt反向激动剂，尽管其水溶性较差。我们利用中的叔丁醇基团合成了一种磷酸酯前药，该前药具有良好的溶解性，在小鼠药代动力学研究中具有出色的暴露量，并且在银屑病小鼠模型中具有显著疗效。