24638-29-7Relevant academic research and scientific papers
Optimization of 5-substituted thiazolyl ureas and 6-substituted imidazopyridines as potential HIV-1 latency reversing agents
Blackmore, Timothy R.,Jacobson, Jonathan,Jarman, Kate E.,Lewin, Sharon R.,Nguyen, William,Purcell, Damian F.,Sabroux, Helene Jousset,Sleebs, Brad E.
, (2020/04/08)
A persistent latent reservoir of virus in CD4+ T cells is a major barrier to cure HIV. Activating viral transcription in latently infected cells using small molecules is one strategy being explored to eliminate latency. We previously described the use of a FlpIn.FM HEK293 cellular assay to identify and then optimize the 2-acylaminothiazole class to exhibit modest activation of HIV gene expression. Here, we implement two strategies to further improve the activation of viral gene expression and physicochemical properties of this class. Firstly, we explored rigidification of the central oxy-carbon linker with a variety of saturated heterocycles, and secondly, investigated bioisosteric replacement of the 2-acylaminothiazole moiety. The optimization process afforded lead compounds (74 and 91) from the 2-piperazinyl thiazolyl urea and the imidazopyridine class. The lead compounds from each class demonstrate potent activation of HIV gene expression in the FlpIn.FM HEK293 cellular assay (both with LTR EC50s of 80 nM) and in the Jurkat Latency 10.6 cell model (LTR EC50 220 and 320 nM respectively), but consequently activate gene expression non-specifically in the FlpIn.FM HEK293 cellular assay (CMV EC50 70 and 270 nM respectively) manifesting in cellular cytotoxicity. The lead compounds have potential for further development as novel latency reversing agents.
Benzimidazole derivatives, their preparation and their application in medicine and pharmacology (by machine translation)
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Paragraph 0391-0392, (2019/07/16)
The invention relates to a new control or inhibit indocyanine 2, 3 - dioxygenase (IDO) activity of the benzimidazole derivatives, their preparation and their application in medicine and pharmacology. Specifically, the invention relates to a compound of general formula (I) compound of formula and its pharmaceutically acceptable salt, containing the compound or its pharmaceutically acceptable salt of the pharmaceutical composition, the use of the compound or its pharmaceutically acceptable salts for treating and/or preventing the relevance of the IDO-mediated disease, especially a tumor of the method and the compound or its pharmaceutically acceptable salts thereof. The invention also relates to the compound or its pharmaceutically acceptable salt or containing the compound or its pharmaceutically acceptable salts for the preparation of a pharmaceutical composition for treating and/or preventing the relevance of the IDO-mediated disease, in particular of the use of the drug in the tumor. Wherein the general formula (I) of each substituent is as defined in the specification. (by machine translation)
ACTIVATORS OF HIV LATENCY
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Page/Page column 73; 74, (2018/04/19)
The present invention relates to novel compounds which active HIV expression in latently infected cells. More particularly, the invention relates to pharmaceutical compositions comprising the novel compounds and their use in activating HIV expression in latently infected cells. Further still, the invention relates to pharmaceutical compositions comprising the novel compounds in combination with anti-HIV therapy compounds and their use in treating HIV infection in both animals and humans. The invention further provides means for preparing the compounds.
4-METHYL-2,3,5,9,9B-PENTAAZA-CYCLOPENTA[A]NAPHTHALENES
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Page/Page column 105-107, (2014/02/16)
The invention relates to 4-methyl-2,3,5,9,9b-pentaaza-cyclopenta[a]naphthalene derivatives of general formula (I) which are inhibitors of phosphodiesterase 2 and/or 10, useful in treating central nervous system diseases and other diseases. In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacture the compounds according to the invention.
4-Methyl-2,3,5,9,9b-pentaaza-cyclopenta[a]naphthalenes
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Paragraph 0611-0614; 0631-0632, (2014/03/21)
The invention relates to 4-methyl-2,3,5,9,9b-pentaaza-cyclopenta[a]naphthalene derivatives of general formula (I) which are inhibitors of phosphodiesterase 2 and/or 10, useful in treating central nervous system diseases and other diseases. In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacture the compounds according to the invention.
NOVEL HETEROCYCLIC DERIVATIVES AND THEIR USES
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Paragraph 0754-0755, (2014/10/29)
The present invention relates to novel heterocyclic compounds useful in preparing drugs for treatment of diseases associated with various functions of the histamine 4 receptor. Especially, the said drugs are useful for treatment of inflammatory diseases, allergy, pain, nasal polyps, rhinitis, chronic sinusitis, nasal congestion, nasal itch, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis, eczema, pruritus, itchy skin, urticaria, idiopathic chronic urticaria, scleroderma, conjunctivitis, keratoconjunctivitis, ocular inflammation, dry eye, cardiac dysfunction, arrhythmia, atherosclerosis, multiple sclerosis, inflammatory bowel disease (including colitis, Crohn's disease, ulcerative colitis), inflammatory pain, neuropathic pain, osteoarthritic pain, autoimmune thyroid disease, immune-mediated (also known as type I) diabetes, lupus, post-operative adhesions, vestibular disorders and cancer.
5-(N-oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: Novel, systemically active and broad spectrum antagonists for NMDA/glycine, AMPA, and kainate receptors
Cai, Sui Xiong,Huang, Jin-Cheng,Espitia, Stephen A.,Tran, Minhtam,Ilyin, Victor I.,Hawkinson, Jon E.,Woodward, Richard M.,Weber, Eckard,Keana, John F.W.
, p. 3679 - 3686 (2007/10/03)
A group of 5-aza-7-substituted-1,4-dihydroquinoxaline-2,3-diones (QXs) and the corresponding 5-(N. oxyaza)-7-substituted QXs were prepared and evaluated as antagonists of ionotropic glutamate receptors. The in vitro potency of these QXs was determined by inhibition of [3H]-5,7- dichlorokynurenic acid ([3H]DCKA) binding to N-methyl-D-aspartate (NMDA)/glycine receptors, [3H]-(S)-α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid ([3H]AMPA) binding to AMPA receptors, and [3H]kainate ([3H]KA) binding to KA receptors in rat brain membranes. 5-(N- Oxyaza)-QXs 12a-e all have low micromolar or submicromolar potency for NMDA/glycine receptors and low micromolar potencies for AMPA and KA receptors. QXs 12a-e display 2-12-fold selectivity for NMDA/glycine receptors compared to AMPA receptors, and ~2-fold difference between AMPA and KA potency. In contrast to other QXs that either show high selectivity for NMDA (such as ACEA 1021) or AMPA (such as NBQX) receptors, these molecules are broad spectrum antagonists of ionotropic glutamate receptors. 7-Nitro-5-(N- axyaza)-QX (12e) is the most potent inhibitor among 12a-e, having IC50 values of 0.69, 1.3, and 2.4 μM at NMDA, AMPA, and KA receptors, respectively. In functional assays on glutamate receptors expressed in oocytes by rat cerebral cortex poly(A+) RNA, 7-chloro-5-(N-oxyaza)-QX (12a) and 7-nitro-5(N-oxyaza)-QX (12e) have K(b) values of 0.63 and 0.31 μM for NMDA/glycine receptors, and are 6- and 4-fold selective for NMDA over AMPA receptors, respectively. 5-(N-Oxyaza)-7-substituted-QXs 12a-e all have surprisingly high in vivo potency as anticonvulsants in a mouse maximal electroshock-induced seizure (MES) model. 7-Chloro-5-(N-oxyaza)-QX (12a), 7- bromo-5-(N-oxyaza)-QX (12b), and 7-methyl-5-(N-oxyaza)-QX (12c) have ED50 values of 0.82, 0.87, and 0.97 mg/kg iv, respectively. The high in vivo potency of QXs 12a-e is particularly surprising given their low log P values (~ -2.7). Separate studies indicate that QXs 12a and 12e are also active in vive as neuroprotectants and also have antinociceptive activity in animal pain models. In terms of in vivo activity, these 5-(N-oxyaza)-7-substituted- QXs are among the most potent broad spectrum ionotropic glutamate antagonists reported.
8-aza, 6-aza and 6,8-diaza-1,4-dihydroquinoxaline-2,3-diones and the use thereof as antagonists for the glycine/NMDA receptor
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, (2008/06/13)
Disclosed is a method of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma or hypoglycemia. The method comprises administering to an animal a compound of the formula: STR1 or a pharmaceutically acceptable salt thereof; wherein n is zero or 1; R 4, R 5, R 6 are independently hydrogen, nitro, amino, halo, haloalkyl, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, azido, acylamino, alkylsulfonyl, aryl, substituted aryl, heteroaryl, alkoxy, trialkylsilyl-substituted alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, a heterocyclic group, a heterocyclicoxy group, aralkoxy, or haloalkoxy; and R c and R d are defined in the specification. These compounds have high binding to the glycine site of the NMDA receptor.
Diaminopyridine compounds and methods of use
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, (2008/06/13)
The present invention relates to compositions and method for inhibiting nonenzymatic cross-linking (protein aging) which contain diaminopyridines and derivates thereof. Accordingly, a composition is disclosed which comprises an agent capable of inhibiting the formation of advanced glycosylation endproducts of target proteins by reacting with the carbonyl moiety of the early glycosylation product of such target proteins formed by their initial glycosylation. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated.
