- HYPOXANTHINE COMPOUND
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PROBLEM TO BE SOLVED: To provide a novel compound having an inhibitory action of prolyl hydroxylase (PHDs) and useful as a therapeutic agent of an inflammatory bowel disease such as ulcerative colitis. SOLUTION: The present invention relates to a hypoxanthine compound represented by the following formula (I) or a pharmacologically acceptable salt thereof. The compound of the present invention or its pharmaceutically acceptable salt has an inhibitory effect of prolyl hydroxylase and is useful as a therapeutic agent for inflammatory bowel disease such as ulcerative colitis. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0087; 0122
(2021/07/17)
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- TLR7/8 AGONISTS AND LIPOSOME COMPOSITIONS
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The present disclosure relates to a method of loading a toll like receptor (TLR)7/8 agonist into a liposome using remote loading and a kit of parts suitable for the loading of a TLR7/8 agonist into a liposome by said method. The present disclosure further relates to a liposome comprising a salt of a TLR7/8 agonist in the liposome interior and to the use of said liposome for stimulation of an immune response and/or treatment of a clinical condition. Finally, the present disclosure relates to a TLR7/8 agonist which is suitable for being remotely loaded into a liposome.
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Page/Page column 13; 78; 123
(2020/02/16)
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- Design, Synthesis, and Immunological Evaluation of a Multicomponent Construct Based on a Glycotripeptoid Core Comprising B and T Cell Epitopes and a Toll-like Receptor 7 Agonist That Elicits Potent Immune Responses
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We present here for the first time the synthesis and immunological evaluation of a fully synthetic three-component anticancer vaccine candidate that consists of a β-glycotripeptoid core mimicking a cluster of Tn at the surface of tumor cells (B epitope), conjugated to the OVA 323-339 peptide (T-cell epitope) and a Toll-like receptor 7 (TLR7) agonist for potent adjuvanticity. The immunological evaluation of this construct and of precursor components demonstrated the synergistic activity of the components within the conjugate to stimulate innate and adaptive immune cells (DCs, T-helper, and B-cells). Surprisingly, immunization of mice with the tricomponent GalNAc-based construct elicited a low level of anti-Tn IgG but elicited a very high level of antibodies that recognize the TLR7 agonist. This finding could represent a potential vaccine therapeutic approach for the treatment of some autoimmune diseases such as lupus.
- Szekely, Thomas,Roy, Olivier,Dériaud, Edith,Job, Aurélie,Lo-Man, Richard,Leclerc, Claude,Taillefumier, Claude
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p. 9568 - 9582
(2018/11/23)
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- High potency of lipid conjugated TLR7 agonist requires nanoparticulate or liposomal formulation
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Conjugation of small molecule agonists of Toll-like receptor 7 (TLR7) to proteins, lipids, or polymers is known to modulate potency, and the physical form or formulation of these conjugates is likely to have a major effect on their immunostimulatory activity. Here, we studied the effect of formulation on potency of a 1,2?di?(9Z?octadecenoyl)?sn?glycero?3?phosphoethanolamine (DOPE) conjugated TLR7 agonist (DOPE-TLR7a) alongside assessing physical form using Dynamic Light Scattering (DLS), Nanosight Particle Tracking (NTA) analysis and Small Angle X-ray Scattering (SAXS). A very high potency of DOPE-TLR7a conjugate (EC50 around 9 nM) was observed either when prepared by direct dilution from DMSO or when formulated into 400–700 nm large multilamella liposomes containing dimethyldioctadecylammonium bromide salt (DDA) and DOPE. When prepared by dissolution in DMSO followed by dilution in aqueous culture medium, 93 ± 5 nm nanoparticles were formed. Without dilution from solution in DMSO, no nanoparticles were observed and no immunostimulatory activity could be detected without this formulation step. SAXS analysis of the conjugate after DMSO dissolution/water dilution revealed a lamellar order with a layer spacing of 68.7 ? which correlates with arrangement in groups of 3 bilayers. The addition of another immunostimulatory glycolipid, trehalose?6,6?dibehenate (TDB), to DOPE:DDA liposomes gave no further increase in immunostimulatory activity beyond that provided by incorporating DOPE-TLR7a. Given the importance of nanoparticle or liposomal formulation for activity, we conclude that the major mechanism for increased potency when TLR7 agonists are conjugated to macromolecules is through alteration of physical form.
- Gadd, Adam J.R.,Castelletto, Valeria,Kabova, Elena,Shankland, Kenneth,Perrie, Yvonne,Hamley, Ian,Cobb, Alexander J.A.,Greco,Edwards, Alexander D.
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p. 268 - 276
(2018/07/31)
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- Phospholipid drug analogs
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Provided in some embodiments are compositions comprising a compound having a structure according to Formula A or Formula B: or a pharmaceutically acceptable salt, tautomer or hydrate thereof, where X2 is a bond or linker, X3 is bond or —PO4—, and X1, R1, R2, R3, and n are described herein. Also provided in some embodiments are methods for making and using such compounds and compositions.
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Page/Page column 36; 39
(2015/11/27)
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- TLR AGONISTS
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The present invention provides for TLR agonist conjugates (compounds) and compositions, as well as methods of using them. The compounds of the invention are broad-spectrum, long-lasting, and non-toxic combination of synthetic immunostimulatory agents, which are useful for activating the immune system of a mammal, preferably a human and can help direct the pharmacophore to the receptor within the endosomes of target cells and enhance the signal transduction induced by the pharmacophore.
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Page/Page column 18; 24
(2008/06/13)
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- 9-Benzyl-6-(dimethylamino)-9H-purines with Antirhinovirus Activity
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A series of 9-benzyl-6-(dimethylamino)-9H-purines and 9-benzyl-2-chloro-6-(dimethylamino)-9H-purines were synthesized and tested in cell culture for activity against rhinovirus type 1B.The 9-benzylpurines that were unsubstituted in the 2-position had weak
- Kelley, James L.,Linn, James A.,Krochmal, Mark P.,Selway, J. W. T.
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p. 2001 - 2004
(2007/10/02)
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