Important Compound Classes
Title
Substituted Imidazo-quinolines as NLRP3 Modulators
Patent Application Number
WO 2018/152396 A1
Publication Date
August 23, 2018
Priority Application
US 62/460,677
US 62/490,881
US 62/573,991
Priority Date
February 17, 2017
April 27, 2017
October 18, 2017
Inventors
Glick, G.; Ghosh, S.; Roush, W. R.; Olhava, E. J.; O’Malley, D.
Assignee Company
Innate Tumor Immunity, Inc.
Biological Target
NLRP3
Summary
Inflammasomes are multiprotein oligomers with pattern recognition receptors that sense tissue damage and microbial infections and also initiate inflammatory responses. Dysregulation of inflammasomes is implicated in various human diseases including cancer, autoinflammatory disorders, and metabolic disorders. Various types of inflammasomes are characterized by receptor molecule or sensor from the nucleotide-binding domain, leucine-rich repeat-containing protein family pyrin and HIN domain-containing protein.
The nucleotide-binding oligomerization domain-like receptors (NLRs) are family of intracellular receptors that detect pathogens associated with molecular patterns and endogenous molecules. A subfamily of NLRs are the NLRPs that include the pyrin domain and their associated proteins, including NLRP1, NLRP3, NLRP4, NLRP6, NLRP7, and NLRP12. The NLRP3 proteins are the best characterized and are associated with the onset and progression of various diseases, including autoinflammatory diseases, multiple sclerosis, metabolic disorders, and so forth.
A number of NLRP3 inflammasome inhibitors are reported and have shown promise in the clinic. In addition to the NLRP3 protein, the NLRP3 inflammasome contains apoptosis-associated speck-like (ASC) and procaspase-1. The interaction between these three proteins may regulate the inflammasome function, including immune activity when needed. For example, in the presence of immune activators such as pathogen-associated molecular patterns (PAMPs), exogenous invaders, or environmental stress, NLRPs are activated and allow interactions of the pyrin domains in the NLRPP3 and the ASC. Conversely, in the absence of immune activators, internal interaction between the leucine-rich repeats and the NACHT domain inhibit interaction between the NLRP3 and the ASC, which prevents the assembly of the inflammasome. A wide array of complex stimuli has been identified that triggers procaspase-1 self-cleavage and induce conversion of cytokines interleukin (IL)-1β and IL-18 to their active forms. In addition, pyroptosis may be triggered, which may lead to inflammation-related cell death. Inappropriate activation of the NLRP3 inflammasome can activate the onset and progression of various disease processes such as metabolic syndrome, atherosclerotic plaque progressions and instability, and hyperglycemia. Activation of the airway epithelium NLRP3 inflammasome is associated with allergic airway disorders, and its expression is believed to be induced by inflammatory cytokines and TLR agonists in myeloid and human bronchial epithelial cells. Reports have shown that reduced IL-18 levels, which lack components of the NLRP3 inflammasome in animal model, eventually led to colorectal tumorigenesis. Thus, IL-1β and IL-18 have potential in the treatment of various types of cancer.
Compounds in this Patent Highlights modulate NLRP3 signaling and may correct or treat deficiency in innate immune activity.
Definitions
R1 = H, unsubstituted C1–6 alkyl, CHO, C(=O)Ra, −C(=O)Ra, −S(O)ORa, −S(O)1–2(Rb), and so forth. (a) = 1–9 ring carbon atoms, (b) = 0–3 ring heteroatoms.
R2 = H and unsubstituted C1–6 alkyl.
R3 = H, unsubstituted C1–2 alkyl.
R4 and R5 = H, halo, cyano, −C(=O)OH, −C(=O)ORa.
R6 and R7 = H, unsubstituted C1–2 alkyl, C3–C5 cycloalkyl.
Key Structures
The inventors described the synthesis and
biological activities of over 380 examples of formula I, which are
represented by the following:
Biological Assay
In vitro human TLR7 and TLR8 binding assays were evaluated using human HEK-Blue cells coexpressing a TLR7 or TLR8 gene.
In vivo pharmacology was assessed in preclinical syngeneic tumor models such as MC38, CT26, and 4TI. The PK/PD relationship was evaluated to assess the profile of the tumor-infiltrating lymphocytes.
Biological Data
The Table below shows activity ranges: A = ≤1
μM; B = >1, ≤20 μM; C = >20, ≤100
μM; D = >100 μM.
Recent Review Articles
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1.
Mastrocola R.; Aragno M.; Alloatti G.; Collino M.; Penna C.; Pagliaro P.. Curr. Med. Chem. 2018, 25, 1294.
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2.
Hafner-Bratkovic I.; Pelegrin P.. Curr. Opin. Immunol. 2018, 52, 8.
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3.
Yang J.; Liu Z.; Ziao T. S.. Cell. Mol. Immunol. 2017, 14, 65.
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4.
Jahan S.; Kumar D.; Chaturvedi S.; Rashid M.; Wahajuddin M.; Khan Y. A.; Goyal S. N.; Patil C. R.; Mohanraj R.; Subramanya S.; Ojha S.. Curr. Med. Chem. 2017, 24, 1645.
The author declares no competing financial interest.