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Exchange proteins directly activated by cAMP (EPAC) as guanine nucleotide exchange factors mediate the effects of the pivotal second messenger cAMP, thereby regulating a wide variety of intracellular physiological and pathophysiological processes. A series of novel 2-(isoxazol-3-yl)-2-oxo-N?-phenyl-acetohydrazonoyl cyanide EPAC antagonists was synthesized and evaluated in an effort to optimize properties of the previously identified high-throughput (HTS) hit 1 (ESI-09). Structure-activity relationship (SAR) analysis led to the discovery of several more active EPAC antagonists (e.g., 22 (HJC0726), 35 (NY0123), and 47 (NY0173)) with low micromolar inhibitory activity. These inhibitors may serve as valuable pharmacological probes to facilitate our efforts in elucidating the biological functions of EPAC and developing potential novel therapeutics against human diseases. Our SAR results have also revealed that further modification at the 3-, 4-, and 5-positions of the phenyl ring as well as the 5-position of the isoxazole moiety may allow for the development of more potent EPAC antagonists.

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Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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The invention relates to a compound of Formula (I) and methods of treating cystic fibrosis comprising the step of administering a therapeutically effective amount of a compound of Formula (I) or II to a patient in need thereof: Formula (I) and Formula (II). The invention relates to the use of substituted oxazole and substituted thiazole compounds in the treatment of cystic fibrosis transmembrane conductance regulator (CFTR) mediated diseases.

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Isoxazole – Wikipedia,
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A compound of the formula (I) STR1 wherein R is a group STR2 R1 is hydrogen, phenyl, C1-20 alkyl, C2-8 alkenyl or C2-8 alkynyl each of which may optionally be substituted; or C3-7 cycloalkyl, X is a divalent group –Y–C=C–, and Y is oxygen or sulphur, have antibacterial and/or antimycoplasmal activity.

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Isoxazole – Wikipedia,
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The invention discloses a substituted heterocyclic compound containing an acylhydrazone skeleton as well as a preparation method and application, of the substituted heterocyclic compound. The invention relates to the field, in particular to a substituted heterocyclic compound containing an acylhydrazone skeleton or a pharmaceutically acceptable salt, a pharmaceutical composition containing the compounds and medical application, in particular to an FAAH inhibitor, and application, in preparation of drugs for preventing or treating diseases related to FAAH, including depression, analgesia, cannabinoid use disorders and other related diseases. (by machine translation)

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Isoxazole – Wikipedia,
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A convenient route has been developed for generation of nitrile oxides in situ from nitroalkanes under very mild conditions using microwave irradiation, using 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and DMAP as catalyst. Isoxazolines and isoxazoles are obtained in very good yields compared to known methods.

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In our endeavour towards the development of effective anticancer therapeutics, a novel series of isoxazole-piperazine hybrids were synthesized and evaluated for their cytotoxic activities against human liver (Huh7 and Mahlavu) and breast (MCF-7) cancer cell lines. Within series, compounds 5l-o showed the most potent cytotoxicity on all cell lines with IC50 values in the range of 0.3?3.7 muM. To explore the mechanistic aspects fundamental to the observed activity, further biological studies with 5m and 5o in liver cancer cells were carried out. We have demonstrated that 5m and 5o induce oxidative stress in PTEN adequate Huh7 and PTEN deficient Mahlavu human liver cancer cells leading to apoptosis and cell cycle arrest at different phases. Further analysis of the proteins involved in apoptosis and cell cycle revealed that 5m and 5o caused an inhibition of cell survival pathway through Akt hyperphosphorylation and apoptosis and cell cycle arrest through p53 protein activation.

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Isoxazole – Wikipedia,
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The xanthine oxidase (XO) plays an important role in producing uric acid, and therefore XO inhibitors are considered as one of the promising therapies for hyperuricemia and gout. We have previously reported a series of XO inhibitors with pyrazole scaffold to extend the chemical space of current XO inhibitors. Herein, we describe further structural optimization to explore the optimal heterocycle by replacing the thiazole ring of Febuxostat with 5 heterocycle scaffolds unexplored in this field. All of these efforts resulted in the identification of compound 8, a potent XO inhibitor (IC50 = 48.6 nM) with novel 2-phenylthiazole-4-carboxylic acid scaffold. Moreover, lead compound 8 exhibited hypouricemic effect in potassium oxonate-hypoxanthine-induced hyperuricemic mice. These results promote the understanding of ligand-receptor interaction and might help to design more promising XO inhibitors.

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Isoxazole – Wikipedia,
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A series of 2-substituted 4-oxo-3-thiazolidinylalkanoic acids bearing an isoxazole nucleus in the 2-position have been prepared.None of the compounds synthesised showed antibacterial activity in vitro.

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Isoxazole – Wikipedia,
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Design and Synthesis of Novel Arylisoxazole-Chromenone Carboxamides: Investigation of Biological Activities Associated with Alzheimer’s Disease

A novel series of hybrid arylisoxazole-chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase (ChE) inhibitory activity based on the modified Ellman’s method. Among synthesized compounds, 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide depicted the most acetylcholinesterase (AChE) inhibitory activity (IC50=1.23 mum) and 5-(3-chlorophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide was found to be the most potent butyrylcholinesterase (BChE) inhibitor (IC50=9.71 mum). 5-(3-Nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide was further investigated for its BACE1 inhibitory activity as well as neuroprotectivity and metal chelating ability as important factors involved in onset and progress of Alzheimer’s disease. It could inhibit BACE1 by 48.46 % at 50 mum. It also showed 6.4 % protection at 25 mum and satisfactory chelating ability toward Zn2+, Fe2+, and Cu2+ ions. Docking studies of 5-(3-nitrophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide and 5-(3-chlorophenyl)-N-{4-[(2-oxo-2H-1-benzopyran-7-yl)oxy]phenyl}-1,2-oxazole-3-carboxamide confirmed desired interactions with those amino acid residues of the AChE and BChE, respectively.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem