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Structure-activity relationship of a series of inhibitors of monoacylglycerol hydrolysis – Comparison with effects upon fatty acid amide hydrolase

A series of 32 heterocyclic analogues based on the structure of 2-arachidonoylglycerol (2-AG) were synthesized and tested for their ability to inhibit monoacylglycerol lipase and fatty acid amide hydrolase activities. The designed compounds feature a hydrophobic moiety and different heterocyclic subunits that mimic the glycerol fragment. This series has allowed us to carry out the first systematic structure-activity relationship study on inhibition of 2-AG hydrolysis. The most promising compounds were oxiran-2-ylmethyl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (1) and tetrahydro-2H-pyran-2- ylmethyl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (5). They inhibited cytosolic 2-oleoylglycerol (2-OG) hydrolysis completely (IC50 values of 4.5 and 5.6 muM, respectively). They also blocked, albeit less potently, 2-OG hydrolysis in membrane fractions (IC50 values of 19 and 26 muM, respectively) and anandamide hydrolysis (IC50 values of 12 and 51 muM, respectively). These compounds will be useful in delineating the importance of the cytosolic hydrolytic activity in the regulation of 2-AG levels and, hence, its potential as a target for drug development.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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Synthesis and anti-cancer activity of ND-646 and its derivatives as acetyl-CoA carboxylase 1 inhibitors

Acetyl-coA carboxylase 1 (ACC1) is the first and rate-limiting enzyme in the de novo fatty acid synthesis (FASyn) pathway. In this study, through public database analysis and clinic sample test, we for the first time verified that ACC1 mRNA is overexpressed in non-small-cell lung cancer (NSCLC), which is accompanied by reduced DNA methylation at CpG island S shore of ACC1. Our study further demonstrated that higher ACC1 levels are associated with poor prognosis in NSCLC patients. Besides, we developed a novel synthetic route for preparation of a known ACC inhibitor ND-646, synthesized a series of its derivatives and evaluated their activity against the enzyme ACC1 and the A549 cell. As results, most of the tested compounds showed potent ACC1 inhibitory activity with IC50 values 3?10 nM. Among them, compounds A2, A7 and A9 displayed strong cancer inhibitory activity with IC50 values 9?17 nM by impairing cell growth and inducing cell death. Preliminary SAR analysis clearly suggested that (R)-configuration and amide group were vital to ACC1 and A549 inhibition, since compound (S)-A1 (the enantiomer of ND-646) had poor activity of ACC1 inhibition and the carboxylic acid ND-630 almost lost anticancer effect on A549 cells. Collectively, these findings indicate that ACC1 is a potential biomarker and target for non-small-cell lung cancer, and ND-646 and its derivatives as ACC1 inhibitors deserve further study for treatment of NSCLC.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration

In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38alpha and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-pi stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-beta in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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Synthesis of n-alkyl terminal halohydrin esters from acid halides and cyclic ethers or thioethers under solvent- and catalyst-free conditions

An efficient and eco-friendly protocol has been developed for the preparation of n-alkyl terminal halohydrin esters under solvent- and catalyst-free conditions. Ring opening of cyclic ethers by organic acid halides affords the 1,4- and 1,5-halohydrins, OH-protected by different acyl groups. The green reaction conditions, simple work-up procedures, high yields and broad substrate scope of the reaction highlight the positive features of this method. This journal is

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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Geminal carboxylic acids and esters thereof, pharmaceutical formulations containing them useful in the treatment of bone dysmetabolism

Compounds of formula I: wherein Ra, Rb, Phi, B and R are as defined in the disclosure, have antagonistic activity on osteoclast hyper-reactivity.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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NOVEL DIHYDROPYRIMIDINOISOQUINOLINONES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS.

A compound according to Formula Ia: wherein L1, and R1 are as described herein. The present invention relates to novel compounds according to Formula I that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions, and methods for the production of these novel compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by adminis?tering a compound of the invention.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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Foundational techniques for catalyst design in the upgrading of biomass-derived multifunctional molecules

The production of fuels and chemicals from renewable lignocellulosic biomass resources has been a major research focus in the last few decades. The most efficient method for synthesizing value-added chemical products from sustainable feedstocks is direct catalytic conversion, however, the multifunctional and highly oxygenated biomass-derived substrates are significantly different from petroleum-based feedstocks. Thus, systematic development of new catalytic materials is required to take advantage of the only substantial source of renewable carbon. In this review, we discuss the foundational methodologies that enable rational catalyst design through the investigation of surface-adsorbate interactions and the elucidation of descriptors for selectivity control. Molecular spectroscopies, efficient and predictive computational modeling, rigorous kinetic investigations, and highly controlled materials synthesis have generated fundamental insights leading to general catalyst design principles in biomass upgrading processes. The application of each technique in biomass research is discussed in the context of several case studies, with a focus on the unique insights available from each technique. Moreover, the interplay among multiple techniques, particularly between experimental and computational methods, is also highlighted. Despite the impressive progress made in the biomass field, major roadblocks still exist due to the complexity in the composition and structure of both substrates and catalysts. We share our perspectives regarding future needs in selective catalytic conversions of multifunctional substrates and methods for accelerating catalyst development.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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A PRODRUG OF 1,1′-(1,6-DIOXO-1,6-HEXANEDIYL)BIS-D-PROLINE

The present invention relates to the compound (2R,2’R)-bis(((((tetrahydro-2H-pyran- 4-yl)oxy)carbonyl)oxy)methyl) 1,1′-adipoylbis(pyrrolidine-2-carboxylate), pharmaceutical compositions comprising the same and the use of the same for treatment of diseases or disorders wherein depletion of serum amyloid P component (SAP) would be beneficial, including amyloidosis, Alzheimer’s disease, type 2 diabetes mellitus and osteoarthritis.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF MIGRAINE

Described herein are compounds useful in the treatment of migraine, which have the general formula: wherein: W is a CH group or a N atom; Z is N or C–R4; B and D are selected independently from CH and N, with the proviso that at least one of B and D is CH and with the further proviso that one of B and D can represent N only when W and Z are both other than N; A is a group of Formula II, III or IV, such that group A contains at least 1 N atom; NR7 is either–NH–or–N=; is a single or double bond; X is a N atom, a CH group or a C(OH) group when is a single bond; or, when is a double bond, a C atom; Y is an NH, N-alkyl, N-benzyl or CH 2 group; U and V each represent a N atom or a CH group, with the proviso that both cannot be N; a and b are, independently, 0 or 1; c is an integer from 0 to 3; d is an integer from 1 to 3; e is an integer from 1 to 2; f is an integer from 0 to 3; g is an integer from 3 to 6 and h is an integer from 2 to 3; such that the sum of c and d is at least 2 and the sum of e and f is at least 2; and salts and solvates thereof.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics

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Inhibitors of epidermal growth factor receptor tyrosine kinase: Novel C-5 substituted anilinoquinazolines designed to target the ribose pocket

A series of novel C-5 substituted anilinoquinazolines, selected on the basis of docking experiments and overlays with ATP in the active site of EGFR tyrosine kinase, have been prepared and found to be potent inhibitors. In vivo pharmacokinetics and disease model activity are discussed.

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Tetrahydropyran – Wikipedia,
Tetrahydropyran – an overview | ScienceDirect Topics