Compounds as NLRP3 inflammasome inhibitors and compositions and uses thereof
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Publication Number
US-12221406-B2
Publication Date
2025-02-11
Expiration Date
Abstract
Scaffold compounds are used to design small molecule compounds and structure-activity relationship studies identify inhibitors of inflammation. Methods include pharmaceutical compositions of the small molecule compounds to inhibit, prevent and treat diseases and conditions associated with inflammation, including multiple sclerosis, Alzheimer's disease, acute myocardial infarction, traumatic brain injury and autoinflammatory diseases.
Core Innovation
The disclosure describes sulfonamide small-molecule inflammasome inhibitors based on Formula I and Formula II scaffolds, encompassing SZ-N3I analogs such as HL16, compound 17, SZ-N3I-88, and SZ-N3I-89, alongside pharmaceutically acceptable salts, solvates, or hydrates thereof. Examples incorporate variations in sulfonamide N-substituents, aromatic substituents, and amide-linked aryl or heteroaryl groups. The compounds inhibit NLRP3 complex formation and associated IL-1β release, with structure–activity observations reporting that 3-thiophene acetamide analog compound 17 exhibits improved potency for IL-1β inhibition.
Evaluated molecules provide candidates for pharmaceutical compositions treating inflammatory conditions, including multiple sclerosis, Alzheimer’s disease, myocardial infarction, traumatic brain injury, and autoinflammatory disorders. In animal models, HL16 substantially suppresses experimental autoimmune encephalomyelitis clinical scores. While compound 17 is characterized for IL-1β reduction, reported findings vary regarding whether NLRC4 and AIM2 signaling is spared or inhibited, and whether blood-brain-barrier permeability is demonstrated.
Claims Coverage
The claim coverage includes one independent claim and one inventive feature.
Compound and pharmaceutically acceptable forms
A compound having the recited chemical structure, and pharmaceutically acceptable salts, solvates, or hydrates thereof.
The independent claim covers the recited compound and its pharmaceutically acceptable salts, solvates, or hydrates.
Stated Advantages
Compound 17 selectively inhibits NLRP3 inflammasome activity while sparing NLRC4 and AIM2 signaling.
The 3-thiophene acetamide analog compound 17 shows improved potency for IL-1β inhibition.
HL16 substantially suppresses EAE clinical scores in mice.
Compound 17 crosses the blood-brain barrier, although reported brain levels are below its in vitro IC50 and its oral bioavailability is low.
Documented Applications
HL16 is evaluated in mice with EAE, where it substantially suppresses clinical scores.
Compound 17 is characterized for selective inhibition of the NLRP3 inflammasome and for blood-brain-barrier permeability.
The compounds are evaluated as inflammasome inhibitors targeting NLRP3, NLRC4, and AIM2, and serve as candidates for pharmaceutical compositions treating NLRP3-associated inflammatory diseases, including Alzheimer’s disease, multiple sclerosis, myocardial infarction, traumatic brain injury, and autoinflammatory conditions.
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