Novel Triazine Derivatives as NLRP3 Inhibitors for Treating Asthma or COPD

InfoMetricsFiguresRef. ACS Medicinal Chemistry LettersASAPArticle This publication is free to access through this site. Learn More CiteCitationCitation and abstractCitation and referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse Patent HighlightJanuary 24, 2025Novel Triazine Derivatives as NLRP3 Inhibitors for Treating Asthma or COPDClick to copy article linkArticle link copied!Ram W. Sabnis*Ram W. SabnisSmith, Gambrell & Russell LLP, 1105 W. Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States*E-mail: [email protected]More by Ram W. Sabnishttps://orcid.org/0000-0001-7289-0581Open PDFACS Medicinal Chemistry LettersCite this: ACS Med. Chem. Lett. 2025, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00020https://doi.org/10.1021/acsmedchemlett.5c00020Published January 24, 2025 Publication History Received 12 January 2025Published online 24 January 2025editorialPublished 2025 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsAbstractClick to copy section linkSection link copied!High Resolution ImageDownload MS PowerPoint SlideProvided herein are novel triazine derivatives as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma or COPD, and processes for preparing such compounds.This publication is licensed for personal use by The American Chemical Society. ACS PublicationsPublished 2025 by American Chemical Society Important Compound Classes TitleTriazine Derivatives as NLRP3 Inhibitors Patent Publication NumberWO 2025/003288 A1URL: https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2025003288&_cid=P12-M5SZQM-50837-1 Publication DateJanuary 2, 2025 Priority ApplicationEP 23182238.8 Priority DateJune 29, 2023 InventorsBon, D.; Bouche, L. A.; Guba, W.; Hargrave, E.; Jaeschke, G.; Johnston, H. J.; Mesch, S. K.; Schnider, C.; Steiner, S.; Tosstorff, A. M. Assignee CompanyF. Hoffmann-La Roche AG, Switzerland, and Hoffmann-La Roche Inc., USA Disease AreaAsthma or COPD Biological TargetNLRP3 SummaryThe (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). The 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 triazine derivatives as NLRP3 inhibitors for the treatment of asthma or chronic obstructive pulmonary disease (COPD). Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment. DefinitionsA = -O- or CH2; R1 = hydroxyalkyl or acetyl;R2 = alkyl; and n = 0 or 1. Key Structures Biological AssayThe NLRP3 THP-1 pyroptosis assay was performed. The compounds described in this application were tested for their ability to inhibit NLRP3. The NLRP3 IC50 values (nM) are shown in the following table. Biological DataThe table below shows representative compounds that were tested for NLRP3 inhibition and the biological data obtained from testing representative examples. ClaimsTotal claims: 16Compound claims: 9Pharmaceutical composition claims: 1Method of treatment claims: 1Method of inhibition claims: 1Use of compound claims: 3 Recent Review ArticlesSee refs (1−5).Author InformationClick to copy section linkSection link copied!Corresponding AuthorRam W. Sabnis, Smith, Gambrell & Russell LLP, 1105 W. Peachtree Street NE, Suite 1000, Atlanta, Georgia 30309, United States, https://orcid.org/0000-0001-7289-0581, Email: [email protected]NotesThe author declares no competing financial interest.ReferencesClick to copy section linkSection link copied! This article references 5 other publications. 1Beucher, L.; Gabillard-Lefort, C.; Baris, O. R.; Mialet-Perez, J. Monoamine oxidases: A missing link between mitochondria and inflammation in chronic diseases. Redox Biol. 2024, 77, 103393, DOI: 10.1016/j.redox.2024.103393 Google ScholarThere is no corresponding record for this reference.2Pan, M.; Yang, J.; Jiang, Z. Inflammasomes and their roles in autoimmune diseases. Rheumatol. Autoimmun. 2024, 4, 197– 217, DOI: 10.1002/rai2.12155 Google ScholarThere is no corresponding record for this reference.3Zhou, H.; Wang, L.; Lv, W.; Yu, H. The NLRP3 inflammasome in allergic diseases: mechanisms and therapeutic implications. Clin. Exp. Med. 2024, 24, 231, DOI: 10.1007/s10238-024-01492-z Google ScholarThere is no corresponding record for this reference.4Sabnis, R. W. Fused Bicyclic Heteroaryl Compounds as NLRP3 Inhibitors for Treating Asthma or COPD. ACS Med. Chem. Lett. 2023, 14, 895– 896, DOI: 10.1021/acsmedchemlett.3c00236 Google ScholarThere is no corresponding record for this reference.5Luo, L.; Zhuang, X.; Fu, L.; Dong, Z.; Yi, S.; Wang, K.; Jiang, Y.; Zhao, J.; Yang, X.; Hei, F. The role of the interplay between macrophage glycolytic reprogramming and NLRP3 inflammasome activation in acute lung injury/acute respiratory distress syndrome. Clin. Transl. Med. 2024, 14, e70098 DOI: 10.1002/ctm2.70098 Google ScholarThere is no corresponding record for this reference.Cited By Click to copy section linkSection link copied!This article has not yet been cited by other publications.Download PDFFiguresReferences Get e-AlertsGet e-AlertsACS Medicinal Chemistry LettersCite this: ACS Med. Chem. Lett. 2025, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://doi.org/10.1021/acsmedchemlett.5c00020Published January 24, 2025 Publication History Received 12 January 2025Published online 24 January 2025Published 2025 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsArticle Views-Altmetric-Citations-Learn about these metrics closeArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.Recommended Articles FiguresReferencesAbstractHigh Resolution ImageDownload MS PowerPoint SlideReferences This article references 5 other publications. 1Beucher, L.; Gabillard-Lefort, C.; Baris, O. R.; Mialet-Perez, J. Monoamine oxidases: A missing link between mitochondria and inflammation in chronic diseases. Redox Biol. 2024, 77, 103393, DOI: 10.1016/j.redox.2024.103393 There is no corresponding record for this reference.2Pan, M.; Yang, J.; Jiang, Z. Inflammasomes and their roles in autoimmune diseases. Rheumatol. Autoimmun. 2024, 4, 197– 217, DOI: 10.1002/rai2.12155 There is no corresponding record for this reference.3Zhou, H.; Wang, L.; Lv, W.; Yu, H. The NLRP3 inflammasome in allergic diseases: mechanisms and therapeutic implications. Clin. Exp. Med. 2024, 24, 231, DOI: 10.1007/s10238-024-01492-z There is no corresponding record for this reference.4Sabnis, R. W. Fused Bicyclic Heteroaryl Compounds as NLRP3 Inhibitors for Treating Asthma or COPD. ACS Med. Chem. Lett. 2023, 14, 895– 896, DOI: 10.1021/acsmedchemlett.3c00236 There is no corresponding record for this reference.5Luo, L.; Zhuang, X.; Fu, L.; Dong, Z.; Yi, S.; Wang, K.; Jiang, Y.; Zhao, J.; Yang, X.; Hei, F. The role of the interplay between macrophage glycolytic reprogramming and NLRP3 inflammasome activation in acute lung injury/acute respiratory distress syndrome. Clin. Transl. Med. 2024, 14, e70098 DOI: 10.1002/ctm2.70098 There is no corresponding record for this reference.