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Interleukin-17 cytokines: Effectors and targets in psoriasis-A breakthrough in understanding and treatment.白细胞介素-17 细胞因子：银屑病的效应物和靶点——理解和治疗的突破。
J Exp Med. 2020 Jan 6;217(1). doi: 10.1084/jem.20191397.
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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.
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Retinoic acid receptor-related orphan receptor gamma-t (RORγt) inhibitors in clinical development for the treatment of autoimmune diseases: a patent review (2016-present).临床开发用于治疗自身免疫性疾病的维甲酸受体相关孤儿受体γt（RORγt）抑制剂：专利审查（2016 年至今）。
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(Inverse) Agonists of Retinoic Acid-Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease.（反向）维甲酸相关孤儿受体 γ 激动剂：免疫反应、炎症和自身免疫性疾病的调节。
Annu Rev Pharmacol Toxicol. 2020 Jan 6;60:371-390. doi: 10.1146/annurev-pharmtox-010919-023711. Epub 2019 Aug 6.
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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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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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Transcription Factor Retinoid-Related Orphan Receptor γt: A Promising Target for the Treatment of Psoriasis.转录因子维 A 酸相关孤儿受体 γt：治疗银屑病的有前途的靶点。
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The Snowballing Literature on Imiquimod-Induced Skin Inflammation in Mice: A Critical Appraisal.关于咪喹莫特诱导小鼠皮肤炎症的文献综述：批判性评价
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RORγ antagonists and inverse agonists: a patent review.RORγ拮抗剂和反向激动剂：专利综述
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Recent progress on nuclear receptor RORγ modulators.核受体RORγ调节剂的最新进展。
Bioorg Med Chem Lett. 2016 Sep 15;26(18):4387-4393. doi: 10.1016/j.bmcl.2016.08.012. Epub 2016 Aug 6.

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。

Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist.

作者信息

Cherney Robert J, Cornelius Lyndon A M, Srivastava Anurag, Weigelt Carolyn A, Marcoux David, Duan James J-W, Shi Qing, Batt Douglas G, Liu Qingjie, Yip Shiuhang, Wu Dauh-Rurng, Ruzanov Max, Sack John, Khan Javed, Wang Jinhong, Yarde Melissa, Cvijic Mary Ellen, Mathur Arvind, Li Sha, Shuster David, Khandelwal Purnima, Borowski Virna, Xie Jenny, Obermeier Mary, Fura Aberra, Stefanski Kevin, Cornelius Georgia, Tino Joseph A, Macor John E, Salter-Cid Luisa, Denton Rex, Zhao Qihong, Carter Percy H, Dhar T G Murali

机构信息

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

出版信息

ACS Med Chem Lett. 2020 Mar 31;11(6):1221-1227. doi: 10.1021/acsmedchemlett.0c00063. eCollection 2020 Jun 11.

DOI:10.1021/acsmedchemlett.0c00063
PMID:32551004
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7294715/
Abstract

Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound , which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound (BMS-986251) was selected as a clinically viable developmental candidate.

摘要

设计、合成了新型三环类似物，并将其作为RORγt反向激动剂进行评估。其中几种化合物在IL-17人全血试验中具有强效，并在小鼠药代动力学研究中表现出优异的口服生物利用度。这导致鉴定出化合物，该化合物在小鼠IL-2/IL-23刺激的药效学模型中显示出对IL-17F产生的剂量依赖性抑制作用。此外，在小鼠棘皮症和咪喹莫特诱导的皮肤炎症模型中对化合物进行了研究，结果表明其疗效强劲，与阳性对照相当。由于其整体表现出色，化合物（BMS-986251）被选为具有临床可行性的开发候选药物。