Small molecule toll-like receptor (TLR) antagonists
2 Assignments
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Accused Products
Abstract
The invention provides methods and compositions useful for modulating signaling through Toll-like receptors. The methods involve contacting a TLR-expressing cell with a small molecule having a core structure including at least two rings. Certain of the compounds are 4-primary amino quinolines. Many of the compounds and methods are useful specifically for inhibiting immune stimulation involving at least one of TLR9, TLR8, TLR7, and TLR3. The methods may have use in the treatment of autoimmunity, inflammation, allergy, asthma, graft rejection, graft versus host disease, infection, sepsis, cancer, and immunodeficiency.
316 Citations
139 Claims
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1-30. -30. (canceled)
- 31. A method of affecting TLR-mediated signaling in response to a TLR ligand, comprising contacting a cell expressing a TLR with an effective amount of a compound of Formula IX
- 33. A method of affecting TLR-mediated immunostimulation in a subject, comprising administering to a subject having or at risk of developing TLR-mediated immunostimulation an effective amount of a compound of Formula IX
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35. A method of inhibiting an immunostimulatory nucleic acid-associated response in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula IX
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36-112. -112. (canceled)
- 113. A quinazoline composition having a structural formula
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125. A method of inhibiting signaling by a Toll-like receptor (TLR), comprising
contacting a cell expressing a functional TLR with an effective amount of quinazoline composition having a structural formula wherein X is a substituted or unsubstituted aryl, alkyl, heterocyclic or styryl group, optionally attached to the quinazoline by a nitrogen, oxygen, or sulfur atom or by a SO or SO2 group; -
Y is absent or is an oxygen atom, a sulfur atom, CR9R10, or NR11, where R9, R10, and R11 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein any one of R9, R10, and R11 optionally is combined with R3 or R4 to form a heterocycle;
L is absent or is a hydrogen atom, an alkyl or alkenyl group containing from 1 to 10 carbons, or an aryl group;
R3 and R4 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein R3 and R4 optionally are combined to form a heterocycle; and
R5, R6, R7, and R8 are each independently a hydrogen atom, a halogen atom, or an alkyl, alkenyl, aryl, heterocyclic, nitro, cyano, carboxy, ester, ketone, amino, amido, hydroxy, alkoxy, mercapto, thio, sulfoxide, sulfone, or sulfonamido group, wherein any pair of R5, R6, R7, and R8 which are adjacent one another optionally are combined to form a heterocycle or a carbocycle, and pharmaceutically acceptable hydrates and salts thereof, to inhibit signaling by the TLR.
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126-127. -127. (canceled)
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128. A method of inhibiting signaling by a Toll-like receptor (TLR), comprising
contacting an immune cell expressing a functional TLR with (a) an effective amount of a TLR signal agonist to stimulate signaling by the TLR in absence of a quinazoline composition, and (b) an effective amount of a quinazoline composition having a structural formula wherein X is a substituted or unsubstituted aryl, alkyl, heterocyclic or styryl group, optionally attached to the quinazoline by a nitrogen, oxygen, or sulfur atom or by a SO or SO2 group; -
Y is absent or is an oxygen atom, a sulfur atom, CR9R10, or NR11, where R9, R10, and R11 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein any one of R9, R10, and R11 optionally is combined with R3 or R4 to form a heterocycle;
L is absent or is a hydrogen atom, an alkyl or alkenyl group containing from 1 to 10 carbons, or an aryl group;
R3 and R4 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein R3 and R4 optionally are combined to form a heterocycle; and
R5, R6, R7, and R8 are each independently a hydrogen atom, a halogen atom, or an alkyl, alkenyl, aryl, heterocyclic, nitro, cyano, carboxy, ester, ketone, amino, amido, hydroxy, alkoxy, mercapto, thio, sulfoxide, sulfone, or sulfonamido group, wherein any pair of R5, R6, R7, and R8 which are adjacent one another optionally are combined to form a heterocycle or a carbocycle, and pharmaceutically acceptable hydrates and salts thereof, to inhibit signaling by the TLR in response to the TLR signal agonist compared with the signaling by the TLR in response to the TLR signal agonist in absence of the quinazoline composition.
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129-132. -132. (canceled)
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133. A method of inhibiting an immune response to an antigenic substance, comprising
contacting an immune cell expressing a functional Toll-like receptor with (a) an effective amount of an antigenic substance to stimulate an immune response to the antigenic substance in absence of a quinazoline composition, and (b) an effective amount of a quinazoline composition having a structural formula wherein X is a substituted or unsubstituted aryl, alkyl, heterocyclic or styryl group, optionally attached to the quinazoline by a nitrogen, oxygen, or sulfur atom or by a SO or SO2 group; -
Y is absent or is an oxygen atom, a sulfur atom, CR9R10, or NR11, where R9, R10, and R11 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein any one of R9, R10, and R11 optionally is combined with R3 or R4 to form a heterocycle;
L is absent or is a hydrogen atom, an alkyl or alkenyl group containing from 1 to 10 carbons, or an aryl group;
R3 and R4 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein R3 and R4 optionally are combined to form a heterocycle; and
R5, R6, R7, and R8 are each independently a hydrogen atom, a halogen atom, or an alkyl, alkenyl, aryl, heterocyclic, nitro, cyano, carboxy, ester, ketone, amino, amido, hydroxy, alkoxy, mercapto, thio, sulfoxide, sulfone, or sulfonamido group, wherein any pair of R5, R6, R7, and R8 which are adjacent one another optionally are combined to form a heterocycle or a carbocycle, and pharmaceutically acceptable hydrates and salts thereof, to inhibit an immune response to the antigenic substance compared with the immune response to the antigenic substance in absence of the quinazoline composition.
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134-137. -137. (canceled)
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138. A method of treating an autoimmune disorder in a subject, comprising
administering to a subject having an autoimmune disorder an effective amount of a quinazoline composition having a structural formula wherein X is a substituted or unsubstituted aryl, alkyl, heterocyclic or styryl group, optionally attached to the quinazoline by a nitrogen, oxygen, or sulfur atom or by a SO or SO2 group; -
Y is absent or is an oxygen atom, a sulfur atom, CR9R10, or NR11, where R9, R10, and R11 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein any one of R9, R10, and R11 optionally is combined with R3 or R4 to form a heterocycle;
L is absent or is a hydrogen atom, an alkyl or alkenyl group containing from 1 to 10 carbons, or an aryl group;
R3 and R4 are each independently a hydrogen atom or an alkyl, alkenyl, or aryl group, wherein R3 and R4 optionally are combined to form a heterocycle; and
R5, R6, R7, and R8 are each independently a hydrogen atom, a halogen atom, or an alkyl, alkenyl, aryl, heterocyclic, nitro, cyano, carboxy, ester, ketone, amino, amido, hydroxy, alkoxy, mercapto, thio, sulfoxide, sulfone, or sulfonamido group, wherein any pair of R5, R6, R7, and R8 which are adjacent one another optionally are combined to form a heterocycle or a carbocycle, and pharmaceutically acceptable hydrates and salts thereof, to treat the autoimmune disorder.
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139-142. -142. (canceled)
Specification