Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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NLRP3 Modulators for the Treatment of Autoinflammatory Disorders Robert B. Kargbo* Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States 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 tumorinfiltrating lymphocytes.
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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 repeatcontaining 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 © XXXX American Chemical Society
Received: September 9, 2018
A
DOI: 10.1021/acsmedchemlett.8b00416 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
ORCID
Robert B. Kargbo: 0000-0002-5539-6343 Notes
The author declares no competing financial interest.
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. 1. Mastrocola, R.; Aragno, M.; Alloatti, G.; Collino, M.; Penna, C.; Pagliaro, P. Curr. Med. Chem. 2018, 25, 1294. 2. Hafner-Bratkovic, I.; Pelegrin, P. Curr. Opin. Immunol. 2018, 52, 8. 3. Yang, J.; Liu, Z.; Ziao, T. S. Cell. Mol. Immunol. 2017, 14, 65. 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.
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DOI: 10.1021/acsmedchemlett.8b00416 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
