Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity

Gong, Hanlin; Weinstein, David; Lu, Zhonghui; Duan, James J.‐W.; Stachura, Sylwia; Haque, Lauren; Karmakar, Ananta; Hemagiri, Hemalatha; Raut, Dhanya Kumar; Gupta, Arun Kumar; Khan, Javed; Camac, Dan; Sack, John S.; Pudzianowski, Andrew T.; Wu, Dauh‐Rurng; Yarde, Melissa; Shen, Ding-Ren; Borowski, Virna; Xie, Jenny; Sun, Huadong; D’Arienzo, Celia; Dabros, Marta; Galella, Michael A.; Wang, Faye; Weigelt, Carolyn A.; Zhao, Qihong; Foster, William; Somerville, John; Salter–Cid, Luisa; Barrish, Joel C.; Carter, Percy H.; Dhar, T. G. Murali

doi:10.1016/j.bmcl.2017.12.006

Cited by 36 publications

(37 citation statements)

References 38 publications

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“…However, it was unknown how RORC2 inhibition might affect the function of Th17-Tregs, cells that are enriched in the intestine and likely beneficial for intestinal homeostasis [27]. Here, we show that an inverse agonist of RORC2 (BMS-336) [34] has a dual role in promoting immune homeostasis; simultaneously inhibiting inflammatory Th17-cell differentiation/effector function and enhancing the stability/function of Th17-Tregs. These data support the rationale for the testing of this compound in IBD and provide new insight into the biology and regulation of human Th17-Tregs.…”

Section: Discussionmentioning

confidence: 81%

“…BMS-336, an inverse agonist of RORC2 [34], has been shown to inhibit Th17 cells by diminishing their signature cytokine production and colitogenic potential in mice [25]. To determine whether BMS-336 could similarly inhibit the expression of RORC2regulated genes in human cells, we isolated Th17, Th17/Th1, and Th1 cells from the peripheral blood of healthy adults (Supporting Information Fig.…”

Section: Bms-336 Inhibits Rorc2-regulated Genes In Human Th17 and Th1mentioning

confidence: 99%

“…T cells, Tregs, PBMCs, and LPMCs were stimulated with ImmunoCult TM Human CD3/CD28 T Cell Activator (StemCell Technologies). BMS-336 (compound 25a [34]) (provided by Bristol-Myers Squibb, New York, NY, USA) was added to cultures at 1 μM, as per previous studies in mice [25], unless stated otherwise. DMSO was added to control cell cultures.…”

Section: Cell Enrichment Isolation and Culturementioning

confidence: 99%

“…On a molecular level, FOXP3 and RORC2 physically interact and antagonize each other's function [31,33] but how RORC2 inverse agonists would affect the biology of human Th17-Tregs was unknown. Here, we used a novel selective RORC2 inverse agonist (BMS-336) [34] that has been validated in preclinical mouse models [25] to investigate the effects of RORC2 inhibition on Th17 conventional T cells (Tconvs) and Th17-Tregs.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function

et al. 2020

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Inflammatory bowel diseases (IBD) are chronic conditions that result from uncontrolled intestinal inflammation. Pathogenic Th17 cells, characterized by production of IL‐17A in the absence of IL‐10, are thought to contribute to this inflammation, but in humans, antibody‐mediated blockade of IL‐17A is an ineffective IBD therapy whereas IL‐23 blockade is effective. Here, we investigated the effects of pharmacological inhibition of RORC2, the Th17 cell lineage‐defining transcription factor, on in vivo‐differentiated human Th17 cells and Th17‐like Tregs (Th17‐Tregs). BMS‐336, a small molecule RORC2 inverse agonist, inhibited expression of RORC2‐regulated genes in peripheral Th17 cells (CD4+CD25–CD127+CXCR3–CCR4+CCR6+) in a dose–dependent manner, with similar inhibitory effects on laminar propria mononuclear cells from IBD and non‐IBD subjects. Exposure of peripheral Th17‐Tregs (CD4+CD25hiCD127loCXCR3–CCR4+CCR6+) to BMS‐336 also inhibited IL‐17A production and prevented inflammatory cytokine‐induced destabilization, as evidenced by preserved FOXP3 expression and epigenetic status of the Treg‐specific demethylation region. In parallel, RORC2 inhibition increased the production of IL‐10 in Th17‐Tregs, resulting in enhanced suppression of inflammatory cytokines from myeloid cells. Thus, via its ability to simultaneously inhibit Th17 cells and enhance the stability and function of Th17‐Tregs, pharmacological inhibition of RORC2 is a promising approach to suppress inflammation and promote immune regulation in IBD.

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Section: Discussionmentioning

confidence: 81%

Section: Bms-336 Inhibits Rorc2-regulated Genes In Human Th17 and Th1mentioning

confidence: 99%

Section: Cell Enrichment Isolation and Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function

et al. 2020

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“…In the previous report, we showed that there were two types of inhibitors which induced C-terminus dislocations. Many RORγ inhibitors, such as ursolic acid (UA), hydrogen-bonded with His479 to restrict the movement of H11 in the C-terminus (PDB code; 5X8S) 14 – 21 . However, Compound A did not hydrogen-bond with His479 on H11, and it was therefore able to lead to larger dislocation of the C-terminus and give a ternary complex with a CoR peptide.…”

Section: Introductionmentioning

confidence: 99%

Ternary crystal structure of human RORγ ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction

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et al. 2018

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Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4+ T cells (Th17 cells). Structure-based drug design has proven fruitful in the development of inhibitors targeting the ligand binding domain (LBD) of RORγ. Here, we present the crystal structure of a novel RORγ inhibitor co-complex, in the presence of a corepressor (CoR) peptide. This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 Å shift of helix 5 (H5) backbone and side-chain conformational changes of Met365 on H5. These conformational changes correlate to reduced CoR peptide binding to RORγ-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders.

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Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists

et al. 2019

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Retinoic-acid-related orphan receptor γt (RORγt) inverse agonists could be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1 a with a flexible linear linker as a novel RORγt inverse agonist. A Ushaped conformation in the complex structure of 1 a with RORγt protein was confirmed. Further improvement of the pharmacokinetic (PK) profiles was required because of the low drug exposure in mice upon oral administration (mouse AUC of 1 a: 27 ng · h · mL À 1 at 1 mg · kg À 1 , p.o.). To improve the PK profiles, conformationally constrained U-shaped scaffolds were investigated. As a result, morpholine analogues with improved PK profiles and high potency were successfully identified. The substituent at the N1 position of the quinazoline moiety was also modified, leading to an enhancement of reporter activity. Consequently, compound 43 (N 2 -(3-chloro-4-cyanophenyl)-N 4 -(3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)morpholine-2,4-dicarboxamide) exhibited improved drug exposure (mouse AUC: 1289 ng · h · mL À 1 at 1 mg · kg À 1 , p.o.). In addition, suppression of IL-17A gene expression by IL-23 stimulation in a mouse pharmacodynamics model was observed for 43. The conformation of 43 with RORγt protein was also confirmed as U-shape by X-ray co-crystal structure analysis. The key interaction that boosts potency is also discussed. . Conversion of the substituent on quinazoline ring. Reagents and conditions:(a) 1-bromo-2-methylpropane, K 2 CO 3 , DMF, 70°C, 51 % (for 40 a); (b) 2iodopropane, Cs 2 CO 3 , DMF, 50°C, 39 %; (for 40 b); (c) Pd/C, H 2 , MeOH or MeOH-THF, rt, 80-87 %; (d) (1) 4-nitrophenyl carbonochloridate, pyridine, THF, rt; (2) 33 (scheme 3), DIEA, DMF, rt, 37-78 %. Scheme 5. The preparation of the optically pure compound 43 and 44. Reagents and conditions:(a) chiral column separation by HPLC. crystal was collected by filtration and washed with cold hexane. 3-(cyclopropylmethyl)-2-isopropoxy-6-nitroquinazolin-4(3H)-one: 1 H NMR (300 MHz, CDCl 3 ) δ 0.42-0.57 (4H, m), 1.17-1.32 (1H, m), 1.47 (6H, d, J = 6.0 Hz), 3.99 (2H, d, J = 7.2 Hz), 5.59 (1H, m), 7.52 (1H, d, J = 8.7 Hz), 8.42 (1H, dd, J = 9.1, 2.6 Hz), 9.06 (1H, d, J = 2.6 Hz); MS (ESI) m/z: 304.2 [M + H] + . 40 b: 1 H NMR (300 MHz, CDCl 3 ) δ 0.42-0.55 (4H, m), 1.24-1.36 (1H, m), 1.65 (6H, d, J = 6.8 Hz), 3.98 (2H, d, J = 7.2 Hz), 5.12 (1H, brs), 7.48 (1H, d, J = 9.1 Hz), 8.45 (1H, dd, J = 9.3, 2.8 Hz), 9.10 (1H, d, J = 2.6 Hz); MS (ESI) m/z: 304.3 [M + H] + . -3-(cyclopropylmethyl)-1-isobutylquinazoline-2,4(1H,3H)dione (41 a). To a solution of 40 a (300 mg, 0.95 mmol) in MeOH (6.0 mL) was added PdÀ C (30 mg, 0.28 mmol) and the mixture was stirred at rt for 5 h under hydrogen atmosphere (1 atm). The mixture was filtered through Celite pad. The filtrate was concentrated in vacuo to give 41 a (235.2 mg, 0.818 mmol, 87 %) as a gray solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.23-0.37 (2H, m), 0.36-0.45 (2H, m), 0.89 (6H, d, J = 6.8 Hz), 1.05-1.30 (1H, m), 2.07 (1H, dt, J = 13.7, 6.8 Hz), ...

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Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORγ/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity

Cited by 36 publications

References 38 publications

Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function

Pharmacological inhibition of RORC2 enhances human Th17‐Treg stability and function

Ternary crystal structure of human RORγ ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction

Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists

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