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This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1- (tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-beta-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-beta-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic beta-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3 knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in treating type 2 diabetes mellitus.

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Reference:
Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.

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Reference:
Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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The reaction rate of a catalyzed reaction is faster than the reaction rate of the uncatalyzed reaction at the same temperature.50675-18-8, Name is Tetrahydropyran-4-carbaldehyde, molecular formula is C6H10O2. In a Patent,once mentioned of 50675-18-8, Product Details of 50675-18-8

[A] a malignant tumor growth lasting, cancer metastasis, tumor relapse suggests an important resistance to the CSC involved in targeting, a compound useful as a new antitumor agent. (I) or a pharmaceutically acceptable compound represented by the formula [a] or a salt. [In the formula, Ra The, such as represents fluorine, n is, 1 – 4 represent, R1 And R2 The, represents a hydrogen atom or the like, L is, represents a bond or the like, the V, C1 – 6 Alkylene represents a, Q is, C6 – 10 The aryl group or the like][Drawing] no (by machine translation)

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Reference:
Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.

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Tetrahydropyran – Wikipedia,
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There are provided compounds of the formula or a pharmaceutically acceptable salt thereof wherein X, M, Y, R1 and R2 are as defined herein. The compounds have activity as anticancer agents.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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We designed and synthesized a series of 2-Ar-8-methyl-5- alkylaminolquinolines as potent corticotropin-releasing factor 1 (CRF 1) receptor antagonists. The structure-activity relationships of substituents at each position (R3, R5, R 5?, and R8) was investigated. By derivatization, three compounds (6, 14b, and 14c) were identified as orally active CRF 1 receptor antagonists.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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Cheap and readily available aqueous formaldehyde was used as a formylating reagent in a homologation reaction with nonstabilized diazo compounds, enabled by UV photolysis of bench-stable oxadiazolines in a flow photoreactor. Various aliphatic aldehydes were synthesized along with the corresponding derivatized alcohols and benzimidazoles. No transition-metal catalyst or additive was required to affect the reaction, which proceeded at room temperature in 80 min.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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Enantioselective N-Heterocyclic Carbene Catalyzed Cyclopentene Synthesis via the beta-Azolium Ylide

Herein we report the cycloisomerization of electron-poor 1,5-dienes via the beta-azolium ylide to give enantioenriched cyclopentenes. The reaction is mediated by a chiral N-heterocyclic carbene (NHC) catalyst, exploits readily available substrates, has good generality (17 examples), and displays excellent enantioselectivity (mostly >94:6). Studies demonstrating the viability of a related dynamic kinetic resolution are reported, as are those with alternate tethers and derivatizations.

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Reference:
Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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SAR exploration at the C-3 position of tetrahydro-beta-carboline sstr3 antagonists

MK-4256, a tetrahydro-beta-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-beta-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.

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Tetrahydropyran – Wikipedia,
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PYRAZOLE COMPOUNDS

The present invention relates to wherein each symbol is as defined in the specification. The compound has a superior mineralocorticoid receptor antagonistic action and is useful as an agent for the prophylaxis or treatment of a disease or condition mediated by the mineralocorticoid receptor activation.

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Reference:
Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics