Discovery of carboxyl-containing biaryl ureas as potent RORγt inverse agonists

Sun, Nannan; Huang, Yafei; Yu, Mingcheng; Zhao, Yunpeng; Chen, Jian; Zhu, Chengzhan; Song, Meiqi; Guo, Huimin; Xie, Qiong; Wang, Yonghui

doi:10.1016/j.ejmech.2020.112536

Cited by 11 publications

(7 citation statements)

References 33 publications

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“…The structural basis for these two targets strongly supports the design of dual RORγt and DHODH inhibitors. Previously, we have reported RORγt inhibitors of diverse chemical series, including biaryl amides, carbazole carboxamides, N -indanyl benzamides, and carboxyl-containing biaryl ureas . Motivated by the dual inhibitor blueprint, we performed high-throughput screening (HTS) of our RORγt compound collection using a 2,6-dichloroindophenol sodium (DCIP) assay to determine the DHODH inhibitory activity and identified 2-aminobenzothiazole compounds, exemplified by 1 , as a dual inhibitor with an IC 50 of 4.52 μM for DHODH and an IC 50 of 2.62 μM for RORγt (from cell-based GAL4 assay).…”

Section: Introductionmentioning

confidence: 99%

Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease

Chen

Liu

et al. 2021

J. Med. Chem.

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Inflammatory bowel disease (IBD) is a multifactorial autoimmune disease, representing a major clinical challenge. Herein, a strategy of dual-targeting approach employing retinoic acid receptor-related orphan receptor γ-t (RORγt) and dihydroorotate dehydrogenase (DHODH) was proposed for the treatment of IBD. Dual RORγt/DHODH inhibitors are expected not only to reduce RORγt-driven Th17 cell differentiation but also to mitigate the expansion and activation of T cells, which may enhance anti-inflammatory effects. Starting from 2-aminobenzothiazole hit 1, a series of 2-aminotetrahydrobenzothiazoles were discovered as potent dual RORγt/DHODH inhibitors. Compound 14d stands out with IC 50 values of 0.110 μM for RORγt and of 0.297 μM for DHODH. With acceptable mouse pharmacokinetic profiles, 14d exhibited remarkable in vivo anti-inflammatory activity and dose-dependently alleviated the severity of dextran sulfate sodium (DSS)-induced acute colitis in mice. Taken together, the present study provides a novel framework for the development of therapeutic agents for the treatment of IBD.

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Section: Introductionmentioning

confidence: 99%

Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease

Chen

Liu

et al. 2021

J. Med. Chem.

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“…After hydrolysis under the basic condition, carboxyl acids 1c–15c were obtained without further purification. The subsequent condensation gave final compounds 1–17 with known sulfonyl benzyl amines 19/20/21 under the routine condition …”

Section: Resultsmentioning

confidence: 99%

Discovery of 2-(Ortho-Substituted Benzyl)-Indole Derivatives as Potent and Orally Bioavailable RORγ Agonists with Antitumor Activity

Liu

Gui

et al. 2021

J. Med. Chem.

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RORγ is a dual-functional drug target, which involves not only induction of inflammation but also promotion of cancer immunity. The development of agonists of RORγ promoting Th17 cell differentiation could provide a novel mechanism of action (MOA) as an immune-activating anticancer agent. Herein, we describe new 2-(ortho-substituted benzyl)-indole derivatives as RORγ agonists by scaffold hopping based on clinical RORγ antagonist VTP-43742. Interestingly, subtle structural differences of the compounds led to the opposite biological MOA. After rational optimization for structure−activity relationship and pharmacokinetic profile, we identified a potent RORγ agonist compound 17 that was able to induce the production of IL-17 and IFNγ in tumor tissues and elicit antitumor efficacy in MC38 syngeneic mouse colorectal tumor model. This is the first comprehensive work to demonstrate the in vivo antitumor efficacy of an RORγ agonist.

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“…18–20 Furthermore, RORγ inverse agonists displayed enhanced efficacy in enzalutamide-resistant tumors. 18,19 Consequently, many RORγ inverse agonists for CRPC have been synthesized, 15–18 the scaffold of which is usually composed of two aromatic rings linked by a linear or a cyclic spacer. This scaffold was consistent with commercially available nonsteroidal anti-androgens (Fig.…”

Section: Introductionmentioning

confidence: 99%

In silico design of RORγ inverse agonists based on 3D-QSAR and molecular docking

Deng

Guo

et al. 2022

New J. Chem.

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Discovery of carboxyl-containing biaryl ureas as potent RORγt inverse agonists

Cited by 11 publications

References 33 publications

Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease

Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease

Discovery of 2-(Ortho-Substituted Benzyl)-Indole Derivatives as Potent and Orally Bioavailable RORγ Agonists with Antitumor Activity

In silico design of RORγ inverse agonists based on 3D-QSAR and molecular docking

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