Discovery of novel pyrazole-containing benzamides as potent RORγ inverse agonists

Wang, Tao; Banerjee, Daliya; Bohnert, Tonika; Chao, Jianhua; Enyedy, Istvan; Fontenot, Jason D.; Guertin, Kevin R.; Jones, Howard; Lin, Edward Yin-Shiang; Marcotte, D.J.; Talreja, Tina; Vloten, Kurt van

doi:10.1016/j.bmcl.2015.05.028

Cited by 35 publications

(18 citation statements)

References 19 publications

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“…8). Besides, recently reported other overall structures use the more linear configuration of UA (Chao et al 2015;Wang et al 2015a;Olsson et al 2016). These previously clarified overall complex structures with the linear binding-form inhibitors can be categorized into the UA type.…”

Section: Discussionmentioning

confidence: 96%

Ternary complex of human RORγ ligand‐binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment

et al. 2017

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Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal structure of a ternary complex containing RORγ ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORγ-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy.

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Section: Discussionmentioning

confidence: 96%

Ternary complex of human RORγ ligand‐binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment

et al. 2017

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“…Wang et al identified a series of novel pyrazole containing benzamides as potent RORγ inverse agonists. Compound 315 was found to be more potent, selective and have adequate profiles RORγ inverse agonists [ 217 ]. A series of novel ethyl-5-amino-3-methylthio-1 H -pyrazole-4-carboxylates were synthesized and were screened for in vivo analgesic and anti-inflammatory activities.…”

Section: Pharmacological Activitiesmentioning

confidence: 99%

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

et al. 2018

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Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.

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“…A number of small‐molecule RORγt modulators such as SR2211, TMP778, GSK805, and GNE‐3500 (Figure ) have been described and showcase the diversity of chemical structures which are able to modulate the receptor . The literature, including patent applications, has been reviewed recently …”

Section: Introductionmentioning

confidence: 99%

“…An umber of small-molecule RORgtm odulators [23] such as SR2211, [24] TMP778, [17] GSK805, [25] and GNE-3500 [26] (Figure 1) have been described and showcase the diversity of chemical structures which are ablet om odulate the receptor. [20,[27][28][29][30] The literature, including patenta pplications, has been reviewed recently. [31][32][33] Benzannulated oxacycles of various sizes have been disclosed by Lycera and Phenex.…”

Section: Introductionmentioning

confidence: 99%

Benzoxazepines Achieve Potent Suppression of IL‐17 Release in Human T‐Helper 17 (T_H17) Cells through an Induced‐Fit Binding Mode to the Nuclear Receptor RORγ

et al. 2015

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RORγt, an isoform of the retinoic acid-related orphan receptor gamma (RORc, RORγ), has been identified as the master regulator of T-helper 17 (TH 17) cell function and development, making it an attractive target for the treatment of autoimmune diseases. Validation for this target comes from antibodies targeting interleukin-17 (IL-17), the signature cytokine produced by TH 17 cells, which have shown impressive results in clinical trials. Through focused screening of our compound collection, we identified a series of N-sulfonylated benzoxazepines, which displayed micromolar affinity for the RORγ ligand-binding domain (LBD) in a radioligand binding assay. Optimization of these initial hits resulted in potent binders, which dose-dependently decreased the ability of the RORγ-LBD to interact with a peptide derived from steroid receptor coactivator 1, and inhibited the release of IL-17 secretion from isolated and cultured human TH 17 cells with nanomolar potency. A cocrystal structure of inverse agonist 15 (2-chloro-6-fluoro-N-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide) bound to the RORγ-LBD illustrated that both hydrophobic interactions, leading to an induced fit around the substituted benzamide moiety of 15, as well as a hydrogen bond from the amide NH to His479 seemed to be important for the mechanism of action. This structure is compared with the structure of agonist 25 (N-(2-fluorophenyl)-4-[(4-fluorophenyl)sulfonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-6-amine ) and structures of other known RORγ modulators.

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Discovery of novel pyrazole-containing benzamides as potent RORγ inverse agonists

Cited by 35 publications

References 19 publications

Ternary complex of human RORγ ligand‐binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment

Ternary complex of human RORγ ligand‐binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Benzoxazepines Achieve Potent Suppression of IL‐17 Release in Human T‐Helper 17 (T_H17) Cells through an Induced‐Fit Binding Mode to the Nuclear Receptor RORγ

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Discovery of novel pyrazole-containing benzamides as potent RORγ inverse agonists

Cited by 35 publications

References 19 publications

Ternary complex of human RORγ ligand‐binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment

Ternary complex of human RORγ ligand‐binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Benzoxazepines Achieve Potent Suppression of IL‐17 Release in Human T‐Helper 17 (TH17) Cells through an Induced‐Fit Binding Mode to the Nuclear Receptor RORγ

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Benzoxazepines Achieve Potent Suppression of IL‐17 Release in Human T‐Helper 17 (T_H17) Cells through an Induced‐Fit Binding Mode to the Nuclear Receptor RORγ