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Agonists of the cannabinoid receptor 1 (CB1) have been suggested as possible treatments for a range of medical disorders including gastroesophageal reflux disease (GERD). While centrally acting cannabinoid agonists are known to produce psychotropic effects, it has been suggested that the CB1 receptors in the periphery could play a significant role in reducing reflux. A moderately potent and highly lipophilic series of 2-aminobenzamides was identified through focused screening of GPCR libraries. Development of this series focused on improving potency and efficacy at the CB1 receptor, reducing lipophilicity and limiting the central nervous system (CNS) exposure while maintaining good oral absorption. Improvement of the series led to compounds having excellent potency at the CB1 receptor and high levels of agonism, good physical and pharmacokinetic properties, and low penetration into the CNS. A range of compounds demonstrated a dose-dependent inhibition of transient lower esophageal sphincter relaxations in a dog model.

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Eleven 5-substituted quinoxalines (NO2, NH2, COOH, OCH3, CH3, OH, F, Cl, Br, I, CN, the latter five not reported previously) have been synthesized by standard methods.Their 13C NMR spectra have been measured in DMSO-d6 and assigned on the basis of substituent parameters, by line widths and by intensities.The chemical shifts compare favorably with those calculated using benzene substituent parameters, and are very close to those of corresponding carbons in 1-substituted phenazines.The correlation with the chemical shifts of the corresponding positions in 1-substituted naphthalenes is also close except for those of carbons 4a and 8a in the quinoxalines which, due to their proximity to nitrogen, are downfield (in some cases 12 ppm) of the signals of the corresponding carbons in naphthalene. 5-Fluoroquinoxaline was also measured in CDCl3, CD3COCD3, CD3CN, CD3OD, C6D6 and CD3COOD.In all solvents an abnormally low 2J(CF) (ca. 12 Hz) was found for C-4a and no C-F spin-spin splitting could be detected for the three-bond coupling of C-8a.Similar abnormalities were found in 2-fluoroaniline and 2-fluoroacetanilide.There are linear relationships between the Q parameter of the substituent and the chemical shift of carbons 4a, 5 and 6.A linear relationship also exists between the chemical shift of C-8 (‘para’ position) and the Hammett ?p parameter of the substituent.

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Chronic hepatitis C virus (HCV) infections are a significant medical problem worldwide. The NS5B Polymerase of HCV plays a central role in virus replication and is a prime target for the discovery of new treatment options. We recently disclosed 1H-benzo[de]isoquinoline-1,3(2H)-diones as allosteric inhibitors of NS5B Polymerase. Structural and SAR information guided us in the modification of the core structure leading to new templates with improved activity and toxicity/activity window.

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The present invention relates to the use of quinazoline derivatives of formula (I) wherein A, B, R1, R2, R3 and R4 are defined herein, and pharmaceutically acceptable salts thereof, for the treatment or prevention of infection by hepatitis C virus.

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Quinoxalines belong to a class of excellent heterocyclic scaffolds owing to their wide biological properties and diverse therapeutic applications in medicinal research. They are complementary in shapes and charges to numerous biomolecules they interact with, thereby resulting in increased binding affinity. The pharmacokinetic properties of drugs bearing quinoxaline cores have shown them to be relatively easy to administer either as intramuscular solutions, oral capsules or rectal suppositories. This work deals with recent advances in the synthesis and pharmacological diversities of quinoxaline motifs which might pave ways for novel drugs development.

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The present invention relates to a method for preparing quinoxaline-5- and 6-carboxylic acids. The method comprises contacting an aqueous suspension of a 5- or 6-hydroxymethyl quinoxaline with oxygen in the presence of a transition metal catalyst, to form the respective quinoxaline-5- or 6-carboxylic acid. The method for oxidizing benzylic methyl groups may also be employed to prepare a wide variety of heterocyclic carboxylic acid compounds.

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The present invention relates to amido-substituted cyclohexane compounds of general formula (I) : in which A, R4, R6, R7, R8, R9, R10 and R11 are as defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

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Quinoxalines belong to a class of excellent heterocyclic scaffolds owing to their wide biological properties and diverse therapeutic applications in medicinal research. They are complementary in shapes and charges to numerous biomolecules they interact with, thereby resulting in increased binding affinity. The pharmacokinetic properties of drugs bearing quinoxaline cores have shown them to be relatively easy to administer either as intramuscular solutions, oral capsules or rectal suppositories. This work deals with recent advances in the synthesis and pharmacological diversities of quinoxaline motifs which might pave ways for novel drugs development.

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A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput (qHTS) screen to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC 50 = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Lastly, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke.

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Agonists of the cannabinoid receptor 1 (CB1) have been suggested as possible treatments for a range of medical disorders including gastroesophageal reflux disease (GERD). While centrally acting cannabinoid agonists are known to produce psychotropic effects, it has been suggested that the CB1 receptors in the periphery could play a significant role in reducing reflux. A moderately potent and highly lipophilic series of 2-aminobenzamides was identified through focused screening of GPCR libraries. Development of this series focused on improving potency and efficacy at the CB1 receptor, reducing lipophilicity and limiting the central nervous system (CNS) exposure while maintaining good oral absorption. Improvement of the series led to compounds having excellent potency at the CB1 receptor and high levels of agonism, good physical and pharmacokinetic properties, and low penetration into the CNS. A range of compounds demonstrated a dose-dependent inhibition of transient lower esophageal sphincter relaxations in a dog model.

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