Amido compounds as RORγt modulators and uses thereof
Inventors
Littman, Dan • Huh, Jun R. • Huang, Ruili • HUANG, Wenwei • Englund, Erika Elaine
Assignees
New York University NYU • US Department of Health and Human Services
Publication Number
US-10561666-B2
Publication Date
2020-02-18
Expiration Date
2031-03-11
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Abstract
Amido compounds are disclosed that have a formula represented by the following: and wherein n1, n2, R1a, R1b, R2, R3, R4, R5, and R6 are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, inflammatory conditions, autoimmune disorders, cancer, and graft-versus-host disease.
Core Innovation
This invention relates to amido compounds capable of modulating RORγt activity and uses of such compounds to treat diseases or conditions related to RORγt activity. Specifically, the compounds are described by various formulae (including formula I, Ia, IIa-IIf, III, and others) encompassing a wide range of substitutions and structural variants. These compounds may be prepared as pharmaceutical compositions and used to prevent or treat conditions causally related to RORγt in mammals, including humans.
The problem being solved arises from the central role of RORγt in immune system development, homeostasis, and inflammatory responses. RORγt is required for differentiation of Th17 cells, which produce cytokines like IL-17, IL-17A, IL-17F, IL-22, and TNFα, all implicated in autoimmune disorders, inflammatory diseases, cancer, and graft-versus-host disease. Dysregulation of RORγt activity leads to several diseases including multiple sclerosis, rheumatoid arthritis, asthma, psoriasis, and Crohn's disease, among others. Existing therapeutic options lack agents that directly modulate RORγt activity, and hence there is a need for novel compounds and methods that can specifically target RORγt to treat related conditions.
The invention provides methods and compositions involving administration of these amido compounds to treat disorders linked to RORγt activity. Additionally, the invention discloses assays, including a Drosophila S2 insect cell-based reporter assay, employing fusion proteins with the yeast GAL4 DNA binding domain and truncated RORγt sequences to identify modulators of RORγt transcriptional activity. These assays enable high-throughput screening for selective RORγt modulators, facilitating identification of specific inhibitors such as digoxin derivatives and other amido compounds with inverse agonist or antagonist activity effective in suppressing Th17 cell differentiation.
Claims Coverage
The patent includes several independent claims relating to methods of treating diseases or conditions causally related to RORγt activity using compounds of various specific chemical formulae.
Methods of treating diseases using compounds of formula III
These methods involve administering to a mammal an effective disease-treating or condition-treating amount of a compound according to formula III, which includes various substituents such as R1a, R1b, R2, R3, R4, R5a, R7a, and R7b, as specified in the claims.
Methods employing compounds with specific substituents R7a and R7b
These methods specify that each of R7a and R7b is independently OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, CN, halo, amido, or haloalkyl.
Methods using compounds of formulae IVa-IVf
These involve administering compounds according to formula IVa, IVb, IVc, IVd, IVe, or IVf for treating diseases related to RORγt activity.
Methods with compounds having t as 1 or 2 and specified R5a substituents
Methods where t is 1 or 2 and each R5a is independently OH, Ph, benzyl, Me, Et, n-Pr, or n-Bu for treatment of RORγt-related conditions.
Methods using compounds of formulae VIa-IXc
Treatment methods utilizing compounds according to formula VIa, VIb, VIc, VId, VIe, VIf, VIIa, VIIb, VIIc, VIIIa, VIIIb, VIIIc, VIIId, VIIIe, IXa, IXb, or IXc.
Methods employing specific listed compounds
Methods of treatment using administration of any one of the specifically listed compounds identified by compound IDs in the claims.
Methods treating a broad range of diseases
Methods for treating autoimmune diseases, inflammatory diseases, arthritis, diabetes, multiple sclerosis, uveitis, rheumatoid arthritis, psoriasis, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, atherosclerosis, H. pylori infections and ulcers, inflammatory bowel disease, Crohn's disease, ulcerative colitis, sprue, food allergies, experimental autoimmune encephalomyelitis, and collagen-induced arthritis.
The independent claims cover methods of treating mammalian diseases causally related to RORγt activity by administering structurally defined amido compounds as described by multiple chemical formulae. The inventive features encompass the specific chemical compositions, substituent patterns, and a broad spectrum of disease indications tied to RORγt modulation.
Stated Advantages
Amido compounds selectively modulate RORγt activity and can suppress Th17 cell differentiation without affecting other T cell lineages, indicating specificity and reduced off-target effects.
The disclosed compounds exhibit potent inverse agonist or antagonist activity on RORγt, providing therapeutic benefit in autoimmune and inflammatory diseases.
The Drosophila S2 cell-based reporter assay provides a cost-effective, high-throughput, sensitive, and selective system for identifying RORγt modulators.
The compounds can be formulated in various pharmaceutical compositions for multiple routes of administration, enabling flexible therapeutic use.
Compounds demonstrate binding directly to human RORγt ligand binding domain, supporting their mechanism of action as specific targeted agents.
Documented Applications
Prevention and treatment of inflammatory conditions.
Treatment of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, asthma, Crohn's disease, and experimental autoimmune encephalomyelitis.
Treatment of cancers related to RORγt activity.
Management of graft-versus-host disease.
Treating conditions related to atherosclerosis, H. pylori infections and ulcers resulting from such infection.
Regulation of circadian rhythm-related disorders and metabolic diseases including obesity and diabetes through RORγt modulation.
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