VTP-43742 is a potent and selective RORγt blocker that demonstrates oral efficacy in a mouse model of autoimmunity through suppression of IL-17A production (THER7P.945)

McGeehan, Gerard M.; Bukhtiyarov, Yuri; Zhao, Yi; Meng, Shi; Noto, Paul; Stadanlick, Jason; Kruk, Barbara; Hardy, Andrew W.; Lipinski, Kerri; Kandpal, Geeta; Algayer, Bethany; Guo, Joan; Guo, Rong R; Marcus, Andrew P.; Lotesta, Stephen D.; Dong, Chen; Fan, Kristi; Jia, Lanqi; Yuan, Jing; Zheng, Yajun; Zhuang, Liujing; Dillard, Lawrence W.; Claremon, David A.; Gregg, Richard E.; Lala, Deepak Anil

doi:10.4049/jimmunol.194.supp.208.5

Cited by 4 publications

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“…Finally, there are considerable costs associated with continuous, long-term treatment of psoriasis, so other approaches may be needed to make treatments more cost effective. Small-molecule antagonists of the key transcription factor RORγt in T17 cells are being designed by several companies, and one has been tested in a short phase IIa study in psoriasis patients (73,74). These and other targeted oral drugs have the potential to reduce the cost of treatment and thus expand access to therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Highly Effective New Treatments for Psoriasis Target the IL-23/Type 17 T Cell Autoimmune Axis

2017

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Psoriasis vulgaris, affecting the skin, is one of the most common organ-specific autoimmune diseases in humans. Until recently, psoriasis was treated by agents or approaches discovered largely through serendipity. Many of the available drugs were inherently quite toxic when used as continuous treatment for many years in this chronic disease. However, an increasing understanding of disease-specific immune pathways has spurred development of pathway-targeted therapeutics during the past decade. Psoriasis is now the most effectively treated human autoimmune disease, with high-level clinical improvements possible in ∼90% of patients using a new generation of drugs that selectively target the IL-23/Type 17 T cell axis. Thus, psoriasis is a model for the success of a translational-medicine approach based on cellular and molecular dissection of disease pathogenesis in humans.

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Section: Discussionmentioning

confidence: 99%

Highly Effective New Treatments for Psoriasis Target the IL-23/Type 17 T Cell Autoimmune Axis

2017

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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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Normal human enthesis harbours conventional CD4+ and CD8+ T cells with regulatory features and inducible IL-17A and TNF expression

et al. 2020

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BackgroundThe human enthesis conventional T cells are poorly characterised.ObjectivesTo study the biology of the conventional T cells in human enthesis.MethodsCD4+ and CD8+ T cells were investigated in 25 enthesis samples using immunofluorescence, cytometrically, bulk RNAseq and quantitative real-time PCR following anti-CD3/CD28 bead stimulation to determine interleukin (IL)-17A and tumour necrosis factor (TNF) levels. T-cell receptor (TCR) repertoires were characterised and a search for putative T-cell reactivity was carried out using TCR3 database. The impact of pharmacological antagonism with retinoic acid receptor-related orphan nuclear receptor gamma t inhibitor (RORγti), methotrexate and phosphodiesterase type 4 inhibitor (PDE4i) was investigated.ResultsImmunofluorescence and cytometry suggested entheseal resident CD4+ and CD8+ T cells with a resident memory phenotype (CD69+/CD45RA-) and tissue residency gene transcripts (higher NR4A1/AhR and lower KLF2/T-bet transcripts). Both CD4+ and CD8+ T cells showed increased expression of immunomodulatory genes including IL-10 and TGF-β compared with peripheral blood T cells with entheseal CD8+ T cells having higher CD103, CD49a and lower SIPR1 transcript that matched CD4+ T cells. Following stimulation, CD4+ T cells produced more TNF than CD8+ T cells and IL-17A was produced exclusively by CD4+ T cells. RNAseq suggested both Cytomegalovirus and influenza A virus entheseal resident T-cell clonotype reactivity. TNF and IL-17A production from CD4+ T cells was effectively inhibited by PDE4i, while RORγti only reduced IL-17A secretion.ConclusionsHealthy human entheseal CD4+ and CD8+ T cells exhibit regulatory characteristics and are predicted to exhibit antiviral reactivity with CD8+ T cells expressing higher levels of transcripts suggestive of tissue residency. Inducible IL-17A and TNF production can be robustly inhibited in vitro.

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VTP-43742 is a potent and selective RORγt blocker that demonstrates oral efficacy in a mouse model of autoimmunity through suppression of IL-17A production (THER7P.945)

Cited by 4 publications

References 0 publications

Highly Effective New Treatments for Psoriasis Target the IL-23/Type 17 T Cell Autoimmune Axis

Highly Effective New Treatments for Psoriasis Target the IL-23/Type 17 T Cell Autoimmune Axis

Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists

Normal human enthesis harbours conventional CD4+ and CD8+ T cells with regulatory features and inducible IL-17A and TNF expression

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