Abstract
Provided herein are novel compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating cardiovascular diseases, and processes for preparing such compounds.
Important Compound Classes
Title
Novel Compounds as Modulators of NLRP3 Inhibition
Patent Publication Number
WO 2024/121086 A1
Publication Date
June 13, 2024
Priority Applications
EP 22211843.2 and EP 23173506.9
Priority Dates
December 7, 2022, and May 16, 2023
Inventors
Bouche, L. A.; Guba, W.; Jaeschke, G.; Johnston, H. J.; Mesch, S. K.; Shannon, J. M.; Steiner, S.
Assignee Company
F. Hoffmann-La Roche AG, Switzerland, and F. Hoffmann-La Roche Inc., USA
Disease Area
Cardiovascular diseases
Biological Target
NOD-like receptor protein 3 (NLRP3)
Summary
The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family NOD-like receptor protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activity is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, Alzheimer’s disease, and atherosclerosis. NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form a large aggregate known as an ASC speck. Polymerized ASC in turn interacts with the cysteine protease caspase-1 to form a complex termed as an inflammasome.
Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. A role for NLRP3 in diseases of the central nervous system and lung diseases is emerging. Furthermore, NLRP3 has a role in the development of liver diseases, kidney diseases, and aging.
The present application describes a series of novel compounds as NLRP3 inhibitors for the treatment of cardiovascular diseases. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
R1 and R5 = the atoms to which they are bonded form either a 4–6-membered heterocycle ring comprising a single O heteroatom or a 4–5-membered cycloalkyl ring;
R2 and R3 = H and alkyl, wherein only one R2 or R3 can be H or alkyl;
R4 = alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl substituted with hydroxy or alkoxy, cycloalkylalkyl substituted with hydroxy, alkoxy, or COOH, a 4–6-membered heterocycle comprising a single O heteroatom, (CH2)nC(O)OH, (CH2)nC(O)OCH3, (CH2)nC(O)NHCH3, heteroarylalkyl, (CH2)nS(O)2CH3 or (CH2)nCN, or (CH2)nC(O)NR′R″; and
R6 = H or OH.
Key Structures
Biological Assay
The NLRP3 THP-1 pyroptosis assay was performed. The compounds described in this application were tested for their ability to inhibit NLRP3. The NLRP3 THP-1 pyroptosis IC50 values (nM) are shown in the following table.
Biological Data
The table below shows representative
compounds that were tested for NLRP3 inhibition and the biological
data obtained from testing representative examples.
Claims
Total claims: 25
Compound claims: 18
Pharmaceutical composition claims: 1
Method of treatment claims: 1
Method of inhibition claims: 1
Use of compound claims: 3
Invention claims: 1
Recent Review Articles
The author declares no competing financial interest.
References
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