Cysteine-dependent inverse agonists of nuclear receptors ROR-gamma/ROR-gamma-t and methods of treating diseases or disorders therewith
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Publication Number
US-12060340-B2
Publication Date
2024-08-13
Expiration Date
Abstract
Provided herein are compounds, compositions and methods for treating and preventing diseases and disorders, comprising administering to patients therapeutically effective amounts of cysteine-dependent inverse agonists of the nuclear receptor RORγ/RORγt. In some such embodiments, the inverse agonists bind to cysteine 476 of a nuclear receptor RORγ in the patient. Also provided are methods, as well as compounds and compositions, for modulating the activity of RORγ and RORγt by binding to the allosteric binding site through a covalent bond. In some aspects, the present disclosure relates to using compounds containing Michael acceptor groups which bind to a cysteine residue in the allosteric binding site such as cysteine 476 in RORγ.
Core Innovation
The invention relates to cysteine-dependent inverse agonists of nuclear receptor RORγ/RORγt for treating or preventing autoimmune diseases. The method comprises administering to a patient a therapeutically effective amount of a cysteine-dependent inverse agonist that binds via the formation of a covalent bond between the inverse agonist and a cysteine of the patient's nuclear receptor RORγ/RORγt. The compounds are defined by a group of a formula with structural constraints, including the bond between carbon atoms 4 and 5 being a single bond or a double bond, and specific substituent definitions for R1, R2, R2′, and R3, together with conditions describing which substituents are absent when certain double bonds are present.
The covalent binding is described as covalent allosteric binding to a cysteine in RORγt, including cysteine 476 in RORγ and cysteine 455 in RORγt. The activity is linked to the presence of a Michael acceptor in the A ring and covalent cysteine engagement. The patent also describes RORγ/RORγt biology with respect to IL-17 and IL-17A, including suppressing IL-17A production and selectively inhibiting Th17 differentiation.
The disclosed approach includes target engagement and selectivity preferences, stating that cysteine-dependent binding to the RORγ cysteine is preferred over binding to the orthosteric LBD pocket, with minimal orthosteric binding and reduced effects on RORα/RORβ. The document further describes evaluation in a RORγt-LBD-GAL4 reporter assay and human CD4+ T-cells, and provides extensive chemical and structural definitions, along with formulation and dosing ranges and routes of administration for pharmaceutical compositions.
Claims Coverage
The provided claim content centers on one independent claim for treating autoimmune disease by administering a cysteine-dependent RORγ/RORγt inverse agonist with covalent cysteine binding and a defined chemical formula. Dependent claims add potency thresholds, target engagement and selectivity requirements, and example autoimmune disease types.
Treating autoimmune disease with covalent cysteine-dependent RORγ/RORγt inverse agonist
Administering to a patient a therapeutically effective amount of a cysteine-dependent inverse agonist of nuclear receptor RORγ/RORγt that binds via the formation of a covalent bond between the inverse agonist and a cysteine of the patient's nuclear receptor RORγ/RORγt, for treating a disease or disorder that is an autoimmune disease.
Inverse agonist defined by formula with carbon 4-5 bond dependent substituent constraints
The inverse agonist comprises a group of a formula wherein the bond between carbon atoms 4 and 5 is a single bond or a double bond, with R1 defined as cyano, heteroaryl (C≤8), substituted heteroaryl (C≤8), —CF3, or —C(O)Ra, and Ra defined as hydroxy, amino, alkoxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), alkylsulfonylamino (C≤8), or substituted versions thereof.
Substituent-variable groups R2 and R2′ with double-bond condition
R2 is hydrogen or various (C≤12) groups, and R2′ is absent, hydrogen, or the same (C≤12) groups, provided that when the bond between carbon atoms 4 and 5 is a double bond then R2′ is absent.
R3 substituent definition and absence rule with double bond
R3 is alkyl (C≤12), alkenyl (C≤12), aryl (C≤12), or aralkyl (C≤12), or substituted versions thereof; and when carbon atoms 4 and 5 are joined by a double bond, then R2′ and the hydrogen atom at carbon atom 5 are absent.
Potency threshold in RORγt-LBD-GAL4 reporter assay
The inverse agonist has activity in an RORγt-LBD-GAL4 reporter assay with an IC50 less than 1 μM.
IL-17A secretion suppression in human CD4+ T-cells assay
The inverse agonist suppresses IL-17A secretion from human CD4+ T-cells with assay IC50 activity less than 500 nM.
Covalent binding to cysteine 476 of RORγ/RORγt
The inverse agonist binds to cysteine 476 of the nuclear receptor RORγ.
Minimal orthosteric binding to the RORγ/RORγt LBD orthosteric pocket
The inverse agonist does not significantly bind to the orthosteric binding pocket in the ligand binding domain (LBD) of RORγ/RORγt.
Crohn’s disease treatment
The autoimmune disease is Crohn’s disease.
Overall, the claims cover treating autoimmune disease by administering a cysteine-dependent RORγ/RORγt inverse agonist that forms a covalent bond with a receptor cysteine and is defined by specific formula constraints. Dependent claims further narrow the method through reporter and cell-based potency thresholds, IL-17A secretion suppression, receptor residue engagement, reduced orthosteric pocket binding, and Crohn’s disease.
Stated Advantages
Covalent, cysteine-dependent inverse agonism of nuclear receptor RORγ/RORγt.
Suppression of Th17 differentiation and IL-17A secretion/release.
In vivo efficacy in a collagen-induced rheumatoid arthritis mouse model with decreased clinical scores and paw thickness.
Suppressing IL-17A production.
Selective inhibition of Th17 differentiation.
Preference for cysteine-dependent binding over binding to the orthosteric LBD pocket.
Reduced effects on RORα/RORβ.
Documented Applications
Treating or preventing an autoimmune disease in a patient by administering a cysteine-dependent inverse agonist of nuclear receptor RORγ/RORγt.
Use in the context of Crohn’s disease as an autoimmune disease.
Use in a collagen-induced rheumatoid arthritis mouse model, with decreased clinical scores and paw thickness.
Administration by oral, intraarterial, or intravenous routes in capsule or tablet forms.
Treating or preventing autoimmune diseases.
Treating autoimmune diseases associated with IL-17, including Crohn’s disease, rheumatoid arthritis, lupus, and psoriasis.
Treating an autoimmune disease in a patient in need.
Treating Crohn’s disease.
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