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Provided herein are quinolines, e.g., a compound of Formula (I) or (IB), pharmaceutical compositions thereof, and methods of their use for treating, preventing, or ameliorating one or more symptoms of an endoplasmic reticulum stress-caused disease. Also provided herein are methods of their use for reducing endoplasmic reticulum stress and modulating the activity of a sarcoplasmic/endoplasmic reticulum Ca2+ ATPase.

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Benzofuran – Wikipedia,
Benzofuran | C8H1645O – PubChem

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Lysine specific demethylase 1 (LSD1) plays a vital role in epigenetic regulation of gene activation and repression in several human cancers and is recognized as a promising antitumor therapeutic target. In this paper, a series of 4-(4-benzyloxy)phenoxypiperidines were synthesized and evaluated. Among the tested compounds, compound 10d exhibited the potent and reversible inhibitory activity against LSD1 in vitro (IC50 = 4 muM). Molecular docking was conducted to predict its binding mode. Furthermore, 10d displayed it could inhibit migration of HCT-116 colon cancer cells and A549 lung cancer cells. Taken together, 10d deserves further investigation as a hit-to-lead for the treatment of LSD1 associated tumors.

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Benzofuran – Wikipedia,
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On the basis of our recently resolved first cocrystal structure of Mdm4 in complex with a small molecule inhibitor (PDB ID 3LBJ), we devised an approach for the generation of potential Mdm4 selective ligands. We performed the Ugi four-component reaction (Ugi-4CR) in 96-well plates with an indole fragment, which is specially designed to mimic Trp23, a key amino acid for the interaction between p53 and Mdm4. Generally the reaction yielded mostly precipitates collected by 96-well filter plates. The best hit compound was found to be active and selective for Mdm4 (Ki = 5 muM, 10-fold stronger than Mdm2). This initial hit may serve as the starting point for designing selective p53-Mdm4 inhibitor with higher affinity.

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Benzofuran – Wikipedia,
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Indolenium salts, which readily undergo cleavage in aqueous alkali to give a monosubstituted acetylene and 1,3,3-trimethyl-2-oxindole, are formed when acyl derivatives of the Fischer base are heated with phosphorus oxychloride.Various aryl- and hetarylacetylenes can be conveniently obtained by this method.

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Benzofuran – Wikipedia,
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A series of nonguanidine N1-activated C4-carboxy azetidinone tryptase inhibitors was prepared by solid-phase methodology to quickly assess the SAR associated with distal functionality on the N1-activating group. From these studies, potent inhibitors with improved specificity were discovered.

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Benzofuran – Wikipedia,
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Imidazolidine and 1,4-diazepane analogs of N-(2-benzofuranyl)methyl- N?-(4-alkoxybenzyl)piperazines were prepared to explore the effect of ring contraction and expansion on sigma receptor affinity and subtype selectivity within a series of cyclic diamines. In vitro receptor binding assays revealed that all cyclic vicinal diamines possessed affinity and selectivity for sigma1 receptors. The imidazolidines possessed nanomolar sigma1 affinities (Ki = 6.45-53.5 nM), and relatively low levels of subtype selectivity (sigma2/sigma1 = 58-237). However, the piperazines and diazepanes achieved picomolar sigma1 interactions, with Ki ranges of 0.05-10.28 and 0.10-0.194 nM, respectively. Moreover, the piperazines and diazepanes showed excellent discrimination over the sigma2 receptor, with sigma1 selectivities of 143-16140 and 220-11542, respectively.

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Here, we described the structural modification of previously identified mu opioid receptor (MOR) antagonist NAN, a 6alpha-N-7?-indolyl substituted naltrexamine derivative, and its 6beta-N-2?-indolyl substituted analogue INTA by adopting the concept of “bivalent bioisostere”. Three newly prepared opioid ligands, 25 (NBF), 31, and 38, were identified as potent MOR antagonists both in vitro and in vivo. Moreover, these three compounds significantly antagonized DAMGO-induced intracellular calcium flux and displayed varying degrees of inhibition on cAMP production. Furthermore, NBF produced much less significant withdrawal effects than naloxone in morphine-pelleted mice. Molecular modeling studies revealed that these bivalent bioisosteres may adopt similar binding modes in the MOR and the “address” portions of them may have negative or positive allosteric modulation effects on the function of their “message” portions compared with NAN and INTA. Collectively, our successful application of the “bivalent bioisostere concept” identified a promising lead to develop novel therapeutic agents toward opioid use disorder treatments.

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This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.

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The C-H bond carboxylation of various aromatic compounds with CO2 was achieved by the deprotonative alumination with a mixed alkyl amido lithium aluminate compound iBu3Al(TMP)Li followed by the NHC-copper-catalyzed carboxylation of the resulting arylaluminum species, which afforded the corresponding carboxylation products in high yield and high selectivity. In addition to benzene derivatives, heteroarenes such as benzofuran, benzothiophene, and indole derivatives are also suitable substrates. Functional groups such as Cl, Br, I, vinyl, amide, and CN could survive the reaction conditions. Some key reaction intermediates such as the copper aryl and isobutyl complexes and their carboxylation products were isolated and structurally characterized by X-ray crystallographic analyses, thus offering important information on the reaction mechanism.

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(2S,3R)-N-[2-(Pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b] furan-2-carboxamide (7a, TC-5619), a novel selective agonist of the alpha7 neuronal nicotinic acetylcholine receptor, has been identified as a promising drug candidate for the treatment of cognitive impairment associated with neurological disorders. 7a demonstrated more than a thousand-fold separation between the affinities for the alpha7 and alpha4beta2 receptor subtypes and had no detectable effects on muscle or ganglionic nicotinic receptor subtypes, indicating a marked selectivity for the central nervous system over the peripheral nervous system. Results obtained from homology modeling and docking explain the observed selectivity. 7a had positive effects across cognitive, positive, and negative symptoms of schizophrenia in animal models and was additive or synergistic with the antipsychotic clozapine. Compound 7a, as an augmentation therapy to the standard treatment with antipsychotics, demonstrated encouraging results on measures of negative symptoms and cognitive dysfunction in schizophrenia and was well tolerated in a phase II clinical proof of concept trial in patients with schizophrenia.

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Benzofuran – Wikipedia,
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