ABSTRACT
The Health Insurance Marketplace was designed to increase the affordability of health insurance. The success of the marketplace depends on people's awareness and use of it. In a statewide mail survey of West Virginians, we found that respondents' awareness of the West Virginia Health Insurance Marketplace increased from 2013 to 2014. However, large percentages of respondents continued to be unaware of the availability of federal subsidies and were unsure of their personal eligibility for these subsidies. It is essential that awareness and enrollment efforts continue and that they be expanded in novel ways to continue growth in access to health insurance through the marketplace.
Subject(s)
Awareness , Health Insurance Exchanges/organization & administration , Adult , Eligibility Determination , Female , Health Insurance Exchanges/economics , Health Policy , Humans , Male , Medical Assistance , Middle Aged , Socioeconomic Factors , West VirginiaABSTRACT
ß-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C ß-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C ß-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.
Subject(s)
Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Cilastatin/chemistry , Drug Discovery , Enzyme Inhibitors/chemistry , Imipenem/chemistry , beta-Lactamase Inhibitors , Cilastatin/pharmacology , Cilastatin, Imipenem Drug Combination , Crystallography, X-Ray , Drug Combinations , Drug Resistance, Bacterial/drug effects , Imipenem/pharmacology , Inhibitory Concentration 50 , Klebsiella/drug effects , Microbial Sensitivity Tests , Models, Biological , Pseudomonas/drug effects , Structure-Activity RelationshipABSTRACT
The bridged monobactam ß-lactamase inhibitor MK-8712 (1) effectively inhibits class C ß-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C ß-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1.
Subject(s)
Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemistry , Monobactams/chemical synthesis , beta-Lactamase Inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Binding Sites , Computer Simulation , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imipenem/pharmacology , Microbial Sensitivity Tests , Monobactams/pharmacology , Protein Structure, Tertiary , Structure-Activity Relationship , beta-Lactamases/metabolismABSTRACT
Bridged monobactam beta-lactamase inhibitors were prepared and evaluated as potential partners for combination with imipenem to overcome class C beta-lactamase mediated resistance. The (S)-azepine analog 2 was found to be effective in both in vitro and in vivo assays and was selected for preclinical development.
Subject(s)
Carbapenems/chemistry , Drug Discovery/methods , Imipenem/chemistry , beta-Lactamase Inhibitors , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Carbapenems/pharmacology , Drug Combinations , Imipenem/pharmacology , Mice , Pseudomonas Infections/drug therapy , Pseudomonas Infections/enzymology , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/physiology , Structure-Activity Relationship , beta-Lactam Resistance/drug effects , beta-Lactam Resistance/physiology , beta-Lactamases/metabolismABSTRACT
A novel class of indole ligands for estrogen receptor alpha have been discovered which exhibit potent affinity and high selectivity. Substitution of the bazedoxifene skeleton to the linker present in the HTS lead 1a provided 22b which was found to be 130-fold alpha-selective and acted as an antagonist of estradiol activity in uterine tissue and MCF-7 cancer cells.
Subject(s)
Estrogen Receptor alpha/antagonists & inhibitors , Indoles/chemistry , Indoles/pharmacokinetics , Breast Neoplasms/drug therapy , Cell Line, Tumor , Estrogen Antagonists/chemistry , Estrogen Antagonists/pharmacology , Female , Humans , Inhibitory Concentration 50 , Ligands , Uterus/drug effectsABSTRACT
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.
Subject(s)
Androstenediol/analogs & derivatives , Androstenediol/pharmacology , Estrogen Receptor beta/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Androstenediol/chemical synthesis , Crystallography, X-Ray , Humans , Ligands , Models, Molecular , Molecular Conformation , Selective Estrogen Receptor Modulators/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).
Subject(s)
Chromans/chemistry , Chromans/pharmacology , Estrogen Receptor alpha/metabolism , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Animals , Binding Sites , Cell Line , Female , Gene Expression/drug effects , Humans , Ligands , Models, Chemical , Molecular Structure , Organ Size , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Uterus/drug effectsABSTRACT
The CphA metallo-beta-lactamase from Aeromonas hydrophilia has been expressed, purified and crystallized by the hanging-drop vapor-diffusion method using ammonium sulfate as the precipitant. The crystals exhibit orthorhombic symmetry (P2(1)2(1)2), with unit-cell parameters a = 40.75, b = 42.05, c = 128.88 A. There is one monomer in the asymmetric unit and the solvent content is estimated to be 44% by volume. A data set extending to 1.8 A has been measured.
Subject(s)
Aeromonas hydrophila/enzymology , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , beta-Lactamases/chemistry , beta-Lactamases/genetics , Bacterial Proteins/isolation & purification , Crystallography, X-Ray , Escherichia coli/enzymology , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Transfection , X-Ray Diffraction , beta-Lactamases/isolation & purificationABSTRACT
A series of dihydrobenzoxathiin SERAMs with alkylated pyrrolidine side chains or alkylated linkers was prepared. Minor modifications in the side chain or linker resulted in significant effects on biological activity, especially in uterine tissue.
Subject(s)
Oxathiins/pharmacology , Pyrrolidines/chemistry , Receptors, Estrogen/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Ligands , Models, Molecular , Oxathiins/chemistry , Receptors, Estrogen/metabolismABSTRACT
The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.
