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NOVEL INHIBITORS OF BETA-LACTAMASE

This invention provides novel beta-lactamase inhibitors of the aryl- and heteroarylsulfonamidomethylphosphonate monoester class having nitrogen-based cations or quarternary ammonium groups. The compounds inhibit three classes of beta-lactamases and synergize the antibacterial effects of beta-lactam antibiotics (e.g., imipenem and ceftazidime) against those micro-organisms normally resistant to the beta-lactam antibiotics as a result of the presence of the Beta-lactamases. Formula (I) or pharmaceutically acceptable salt thereof.

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BENZODIOXEPINE AND BENZODIOXINE COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN FOR THE TREATMENT OF DIABETES

The present invention relates to compounds of formula I or II, or pharmaceutically acceptable salts thereof, that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

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gamma-Radiolysis of Aqueous Benzothiophene Solutions

gamma-Radiolysis of aqueous benzothiophene solutions saturated with N2O has been studied.In the absence of other reagents, the only products detected are 2- and 3-hydroxybenzothiophene and their corresponding lactonic and ketonic tautomers and a small amount of dimeric species.In the presence of potassium hexacyanoferrate or sodium hydroxide, however, products attributable to hydroxylation at all six available carbon sites are detected and dimer formation is reduced.Analysis of the experimental data suggests that both benzothiophene and its hydroxylation products are efficient scavengers for the radiation-produced OH radicals and that the initial yield of hydroxylation products is equal to that of hydroxyl radicals.Consistent with the electrophilic characteristics of the OH radical, k(OH+C8H6S):k(OH+C8H5SOH)=0.5+/-0.1.All six available carbon sites are capable of forming OH adducts, but the radicals formed by addition to the 4, 5, 6, and 7 positions tend to revert to the original compound or its ion in a neutral or acidic medium.In the case of the adducts formed by addition to the thiophene ring, on the other hand, the 3 position is seen to be favored, possibly as the result of the preservation of the aromatic benzene resonance structure.

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PYRIMIDINE DERIVATIVES AS PGE2 RECEPTOR MODULATORS

The present invention relates to pyrimidine derivatives of formula (I) wherein (R1)n, R3, R4a, R4b, R5a, R5b and Ar1 are as described in the description and their use in the treatment of cancer by modulating an immune response comprising a reactivation of the immune system in the tumor. The invention further relates to novel benzofurane and benzothiophene derivatives of formula (II) and their use as pharmaceuticals, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as modulators of the prostaglandin 2 receptors EP2 and/or EP4.

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IN VIVO IMAGING OF SULFOTRANSFERASES

Radiolabeled tracers for sulfotransferases (SULTs), their synthesis, and their use are provided. Included are substituted phenols, naphthols, coumarins, and flavones radiolabeled with 18F, 123I, 124I, 125I, or 11C. Also provided are in vivo techniques for using these and other tracers as analytical and diagnostic tools to study sulfotransferase distribution and activity, in health and disease, and to evaluate therapeutic interventions.

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Synthesis and biological evaluation of novel small non-peptidic HIV-1 PIs: The benzothiophene ring as an effective moiety

Synthesis and biological evaluation of a new series of potential HIV-1 protease inhibitors incorporating different heterocycles are described. The variation of heteroatom in such molecules has displayed totally different biological activities and a benzothiophene containing inhibitor has shown high potency against wild type HIV-1 protease with IC50 = 60 nM, thanks to the lower desolvation penalty to be payed by such hydrophobic moiety.

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Completely regioselective direct C-H functionalization of benzo[b]thiophenes using a simple heterogeneous catalyst

The first completely selective C3 C-H arylation of benzo[b]thiophenes is reported, demonstrating previously unexploited reactivity of palladium. Benzo[b]thiophenes are coupled with readily available aryl chlorides using a ligand-free, dual catalytic system of heterogeneous Pd/C and CuCl. The reaction is operationally simple and insensitive to air and moisture, and it provides valuable products with complete selectivity. Significant investigations into the nature of the active catalytic species and mechanistic considerations are discussed.

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Toluene dioxygenase-catalyzed cis-dihydroxylation of benzo[b]thiophenes and benzo[b]furans: Synthesis of benzo[b]thiophene 2,3-oxide

Enzymatic cis-dihydroxylation of benzo[b]thiophene, benzo[b]furan and several methyl substituted derivatives was found to occur in both the carbocyclic and heterocyclic rings. Relative and absolute configurations and enantiopurities of the resulting dihydrodiols were determined. Hydrogenation of the alkene bond in carbocyclic cis-dihydrodiols and ring-opening epimerization/reduction reactions of heterocyclic cis/trans-dihydrodiols were also studied. The relatively stable heterocyclic dihydrodiols of benzo[b]thiophene and benzo[b]furan showed a strong preference for the trans configuration in aqueous solutions. The 2,3-dihydrodiol metabolite of benzo[b]thiophene was utilized as a precursor in the chemoenzymatic synthesis of the unstable arene oxide, benzo[b]thiophene 2,3-oxide.

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Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates

This work focuses on the development of specific substrates for estrogen sulfotransferase (SULT1E1) to produce molecular imaging probes for this enzyme. SULT1E1 is a key enzyme in estrogen homeostasis, playing a central role in the prevention and development of human disease. In vitro sulfation assays showed alkyl and aryl substitutions to a fused heterocyclic system modeled after beta-naphthol (betaN), based on compounds that interact with the estrogen receptor, rendered several molecules with enhanced specificity for SULT1E1 over SULT1A1*1, SULT1A1*2, SULT1A3, and SULT2A1. Several 6-hydroxy-2-arylbenzothiazoles tested demonstrated excellent affinity – V max/Km ratios – and specificity for SULT1E1. Km values ranged from 0.12-2.36 muM. A strong correlation was observed between polarity of the 4?-sustituent on the 2-aryl moiety (Hammett sigmap) and the log(Vmax/Km) (r = 0.964). Substrate sensitivity is influenced by the acidity of the 6-phenolic group demonstrated by correlating its 1H NMR chemical shift (deltaOH) with the log(V max/Km) (r = 0.963). Acidity is mediated by the electron withdrawing capacity of the 4?-substituent outlined by the correlation of the C-2 13C NMR chemical shift (deltaC2) with the log(Vmax/Km) (r = 0.987). 2-[4-(Methylamino)phenyl]-6- hydroxybenzothiazole (2b) was radiolabeled with carbon-11 (11C-(2b)) and used in vivo for microPET scanning and tissue metabolite identification. High PET signal was paralleled with the presence of radiolabeled 11C-(2b)-6-O-sulfate and the SULT1E1 protein detected by western blot. Because this and other members of this family presenting specificity for SULT1E1 can be labeled with carbon-11 or fluorine-18, in vivo assays of SULT1E1 functional activity are now feasible in humans.

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Structural Evolution and Pharmacology of a Novel Series of Triacid Angiotensin II Receptor Antagonists

cis-4-(4-Phenoxy)-1-<1-oxo-2(R)-<4-<(2-sulfobenzoyl)amino>-1H-imidazol-1-yl>octyl>-L-proline derivatives represent a novel class of potent nonpeptide angiotensin II (Ang II) receptor antagonists.These compounds evolved from directed structure-activity relationship (SAR)studies on a lead identified by random screening.Further SAR studies revealed that acidic modification of the 4-phenoxy ring system produced a series of triacid derivatives possessing oral activity in pithed rats.The most potent compound, cis-4-<4-(phosphonomethyl)phenoxy>-1-<1-oxo-2(R)-<4-<(2-sulfobenzoyl)amino>-1H-imidazol-1-yl>octyl>-L-proline (1e), inhibited the pressor response to exogenously administered Ang II for periods up to 8 h following oral dosing.The antihypertensive activity of 1e was evaluated in the Lasix-pretreated conscious spontaneously hypertensive rat (SHR) where it produced a dose-dependent fall in blood pressure following oral dosing lasting > 12 h.Antagonists such as 1e may serve as useful therapeutic agents for the treatment of hypertension as well as for studying the role of Ang II in various disease states.

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