Patent•
Cyclic di-nucleotide compounds as sting agonists
11 Aug 2016-
TL;DR: In this article, a class of polycyclic compounds of general formula (II), of general form (II'), or of general condition (II) was defined, which may be useful as inductors of type I interferon production, specifically as STING active agents.
Abstract: A class of polycyclic compounds of general formula (II), of general formula (II'), or of general formula (II"), wherein Base 1 , Base 2 , Y, Y a , X a , X a1 , X b , X b1 , X c , X c1 , X d , X d1 , R 1 , R 1a , R 2 , R 2a , R 3a , R 4 , R 4a , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , and R 8a are defined herein, that may be useful as inductors of type I interferon production, specifically as STING active agents, are provided. Also provided are processes for the synthesis and use of compounds.
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TL;DR: How increased access to novel biotransformations and the rise of cascade biocatalysis allowed fundamentally new syntheses of novel medicines, representing progress toward more sustainable pharmaceutical manufacturing is illustrated.
92 citations
Patent•
02 Jun 2015TL;DR: A compound of formula (I) or a pharmaceutically acceptable salt and tautomers thereof, compositions, combinations and medicaments containing said compounds and processes for their preparation is defined in this article.
Abstract: A compound of formula (I) or a pharmaceutically acceptable salt and tautomers thereof, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, in the treatment of diseases and conditions in which modulation of STING (Stimulator of Interferon Genes) is beneficial, for example inflammation, allergic and autoimmune diseases, infectious diseases, cancer and as vaccine adjuvants
75 citations
Patent•
09 Sep 2015
TL;DR: In this article, a cyclic dinucleotide compound of Formula (I) was described, where X 1 is H or F; X 2 is H and X 3 is F; at least one among X 1 and X 2 was a fluorine atom; Z is OH, OR 1, SH or SR 1, wherein: R 1 is Na or NH 4, or R 2 is an enzyme-labile group which provides OH or SH in vivo such as pivaloyloxymethyl; B 1 and B 2 are bases chosen from Adenine, Hypox
Abstract: The invention concerns a cyclic dinucleotide compound of Formula (I) wherein X 1 is H or F; X 2 is H or F; at least one among X 1 and X 2 is a fluorine atom; Z is OH, OR 1 , SH or SR 1 , wherein: R 1 is Na or NH 4 , or R 1 is an enzyme-labile group which provides OH or SH in vivo such as pivaloyloxymethyl; B 1 and B 2 are bases chosen from Adenine, Hypoxanthine or Guanine, and B 1 is a different base than B 2 and a pharmaceutically acceptable salt thereof. The invention also concerns pharmaceutical compositions comprising said cyclic dinucleotide, as well as their use in the treatment of a bacterial infection, a viral infection or a cancer.
67 citations
TL;DR: The current understanding of STING structure is summarized, the status quo of STings modulators is surveyed, established bioassay methods are compared, the chemical structures and bioactivities of agonists and inhibitors are reviewed, and suggestions and insights for the future exploitation of STing modulators are proposed.
Abstract: Stimulator of interferon genes (STING) is an adaptor protein that induces the secretion of type I interferons and proinflammatory cytokines and is triggered by cytosolic DNA of pathogen and host origins. Given that STING is a mediator in the immune system, pharmacological modulation of STING has shown viable therapeutic effects for pathogen infection, cancer, and inflammatory diseases. In the past decade, the substantial development in this field has encouraged the discovery of STING modulators. Here, we will summarize the current understanding of STING structure, survey the status quo of STING modulators, compare established bioassay methods, review the chemical structures and bioactivities of agonists and inhibitors, and propose suggestions and insights for the future exploitation of STING modulators.
59 citations
Patent•
17 Mar 2017TL;DR: In this article, cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy are discussed.
Abstract: Disclosed are cyclic-di-nucleotide cGAMP analogs, methods of synthesizing the compounds, pharmaceutical compositions comprising the compounds thereof, and use of compounds and compositions in medical therapy.
57 citations
References
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Book•
01 Jan 1985
TL;DR: The 17th edition of Remington's pharmaceutical sciences is organized as its immediate predecessors, adhering to the concept of division into 9 parts, each subdivided into several chapters as mentioned in this paper.
Abstract: The 17th edition of Remington's pharmaceutical sciences is organized as its immediate predecessors, adhering to the concept of division into 9 parts, each subdivided into several chapters Every chapter in the book has been revised, rewritten and updated, and a new chapter on dissolution appears During revision, all chapters were thoroughly reviewed to eliminate unessential duplication of material and thus recover space sorely needed for new material A number of halftone photographs have been replaced by schematic drawings or "blow-apart" drawings which better explain the construction or operation of equipment or apparatus Practically all the structural formulas depicted in the drug monographs have been replaced with standard USAN structures for uniformity and clarity All CAS registry numbers and molecular formulas were checked and molecular weights recalculated by computer to insure accuracy to the number of significant figures indicated The 17th edition contains 100 pages of additional material besides that gained through streamlining several chapters It is estimated that 200 pages of new material has been incorporated in the book with an actual physical increase of fewer that 100 pages
16,204 citations
Book•
01 Jan 1994
TL;DR: The Handbook of Pharmaceutical Excipients is internationally recognised as the authoritative source of information on pharmaceutical excipients giving a comprehensive guide to uses, properties and safety.
Abstract: Since 1986, the "Handbook of Pharmaceutical Excipients" has been the essential reference for those involved in the development, production, control, or regulation of pharmaceutical preparations. Published jointly by the American Pharmacists Association and the Pharmaceutical Press, a division of the Royal Pharmaceutical Society of Great Britain, London, UK, this new edition is a comprehensive guide to the uses, properties, and safety of pharmaceutical excipients.
7,329 citations
TL;DR: Results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP, which belongs to the nucleotidyltransferase family.
Abstract: The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.
3,096 citations
TL;DR: Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity, and cGAMP functions as an endogenous second messenger in metazoans and triggers interferon production in response to cytosolicDNA.
Abstract: Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity. This DNA signaling pathway requires the adaptor protein STING and the transcription factor IRF3, but the mechanism of DNA sensing is unclear. We found that mammalian cytosolic extracts synthesized cyclic guanosine monophosphate–adenosine monophosphate (cyclic GMP-AMP, or cGAMP) in vitro from adenosine triphosphate and guanosine triphosphate in the presence of DNA but not RNA. DNA transfection or DNA virus infection of mammalian cells also triggered cGAMP production. cGAMP bound to STING, leading to the activation of IRF3 and induction of interferon-β. Thus, cGAMP functions as an endogenous second messenger in metazoans and triggers interferon production in response to cytosolic DNA.
1,667 citations
TL;DR: It is demonstrated that STING binds directly to radiolabelled cyclic diguanylate monophosphate (c-di-GMP), and it is shown that unlabelledcyclic dinucleotides, but not other nucleotides or nucleic acids, compete with c-di -GMP for binding to STING.
Abstract: The innate immune system detects infection by using germline-encoded receptors that are specific for conserved microbial molecules. The recognition of microbial ligands leads to the production of cytokines, such as type I interferons (IFNs), that are essential for successful pathogen elimination. Cytosolic detection of pathogen-derived DNA is one major mechanism of inducing IFN production, and this process requires signalling through TANK binding kinase 1 (TBK1) and its downstream transcription factor, IFN-regulatory factor 3 (IRF3). In addition, a transmembrane protein called STING (stimulator of IFN genes; also known as MITA, ERIS, MPYS and TMEM173) functions as an essential signalling adaptor, linking the cytosolic detection of DNA to the TBK1-IRF3 signalling axis. Recently, unique nucleic acids called cyclic dinucleotides, which function as conserved signalling molecules in bacteria, have also been shown to induce a STING-dependent type I IFN response. However, a mammalian sensor of cyclic dinucleotides has not been identified. Here we report evidence that STING itself is an innate immune sensor of cyclic dinucleotides. We demonstrate that STING binds directly to radiolabelled cyclic diguanylate monophosphate (c-di-GMP), and we show that unlabelled cyclic dinucleotides, but not other nucleotides or nucleic acids, compete with c-di-GMP for binding to STING. Furthermore, we identify mutations in STING that selectively affect the response to cyclic dinucleotides without affecting the response to DNA. Thus, STING seems to function as a direct sensor of cyclic dinucleotides, in addition to its established role as a signalling adaptor in the IFN response to cytosolic DNA. Cyclic dinucleotides have shown promise as novel vaccine adjuvants and immunotherapeutics, and our results provide insight into the mechanism by which cyclic dinucleotides are sensed by the innate immune system.
1,251 citations