The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy ...underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P′, P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.
Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second ...generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH ...503034 (1), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation of the P′ secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats.
A practical and efficient route toward synthesis of amino acid derivatives containing β-quaternary center has been developed using diastereoselective Strecker reaction. The method was employed for ...preparation of >100
g of β-methylcyclohexyl glycine derivative,
21. Incorporation of some of the hindered amino acid derivatives at the P3 position resulted in potent HCV NS3 serine protease inhibitors.
A practical and efficient route toward synthesis of amino acid derivatives containing β-quaternary center has been developed using diastereoselective Strecker reaction. The method was employed for preparation of >100
g of β-methylcyclohexyl glycine derivative,
21. Incorporation of some of the hindered amino acid derivatives at the P3 position resulted in potent HCV NS3 serine protease inhibitors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Laboratory experiments were conducted to compare the degradation of low and high quality concrete under conditions simulating sewer pipes with and without bacteria. Small concrete samples were ...exposed to hydrogen sulfide, multiple species of bacteria found in corroding sewer pipes and artificial wastewater. Experiments without bacteria were used as controls. The corrosion rates of the concrete samples exposed to bacteria over 227
days were 0.08
mm/yr (millimeters per year) for the concrete from a domestic manufacturer with moderate strength and a lower water–cement ratio (Low-w/c) versus 0.208
mm/yr for the concrete samples from a foreign country with low strength and a higher water–cement ratio (High-w/c). The (Low-w/c) concrete was more resistant to the biodegradation even though a lower pH was attained for its bioactive systems. Experiments showed the influence of biogenic sulfuric acid production on short term corrosion rates.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The action of molecular catalysts comprises multiple microscopic kinetic steps whose nature is of central importance in determining catalyst activity and selectivity. Single-molecule microscopy ...enables the direct examination of these steps, including elucidation of molecule-to-molecule variability. Such molecular diversity is particularly important for the behavior of molecular catalysts supported at surfaces. We present the first combined investigation of the initiation dynamics of an operational palladium cross-coupling catalyst at the bulk and single-molecule levels, including under turnover conditions. Base-initiated kinetics reveal highly heterogeneous behavior indicative of diverse catalyst population. Unexpectedly, this distribution becomes more heterogeneous at increasing base concentration. We model this behavior with a two-step saturation mechanism and identify specific microscopic steps where chemical variability must exist in order to yield observed behavior. Critically, we reveal how structural diversity at a surface translates into heterogeneity in catalyst behavior, while demonstrating how single-molecule experiments can contribute to understanding of molecular catalysts.
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The aim of this research is to analyse the performance of the extended producer responsibility model for the management of end-of-life tires (ELTs) in Ecuador that has been implemented since 2013. ...For this research, we conducted case studies of, and subsequently, a comparative analysis between, the ELT management system in Ecuador with respect to the ELT management models in Colombia and Brazil. Our findings show that although the programme implementation represented a significant advance in Ecuador's waste management system there are important challenges that should be considered in future adaptations of the programme. Among the measures that can be adopted to improve the ELT management system are the consolidation and stimulation of the market for products made from ELT waste; promotion of other productive sectors linked to the creation of new products and sectors that generate complementary products; enhancement of the generation, socialization and access to knowledge of the waste by-products for micro-, small- and medium-sized enterprises; increase the tire consumer fee, known as 'Ecovalor' and improvement of the quality and availability of information and indicators regarding ELT management. In this sense, the experiences of Colombia and Brazil show important lessons for the Ecuadorian case.
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Proper treatment of tuberculosis requires a combination of drugs to which the causative organism is susceptible. In this report, genotypic assessment of antimicrobial susceptibility of more than ...10,000
M. tuberculosis
isolates was correlated with phenotypic test results.
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