Discovery of novel pyridinones as MGAT2 inhibitors for the treatment of metabolic disorders.

Inhibition of monoacylglycerol transferase 2 (MGAT2) has recently emerged as a potential therapeutic strategy for the treatment of metabolic diseases such as obesity, diabetes and non-alcoholic steatohepatitis (NASH). Metabolism studies with our clinical lead (1) suggested variability in in vitro glucuronidation rates in liver microsomes across species, which made projection of human doses challenging. In addition, the observation of deconjugation of the C3-C4 double bond in the dihydropyridinone ring of 1 in solution had the potential to complicate its clinical development. This report describes our lead optimization efforts in a novel pyridinone series, exemplified by compound 33, which successfully addressed both of these potential issues.

Causal correlation between energy use and carbon emissions in selected emerging economies-panel model approach.

Fossil fuels used in energy mix continues to dictate world heat usage. Demand for heat is considered as substantial contributor to carbon emissions and energy-related emissions equivalent to 12.5 Gt of carbon emissions. Data on heat is limited and therefore, a study on the causal correlation between energy use and emissions would provide policy guidance on how to decarbonize the heat sector to achieve Paris's Greenhouse Effect Treaty. Most empirical works aggregated energy consumption and ignore spatial dependence and heterogeneity in a panel dataset. Our study, however, disaggregated energy into renewable and non-renewable to find their distinct influence on emissions, which were tested for spatial dependence and heterogeneity and applied potential emissions as environmental impact. Using FGLS and PCSE estimators for the period 1971-2013, our findings revealed that the increase in renewable energy use and industrialization improves the ecological structure of emerging economies while the increase in population, economic expansion, and non-renewable energy use increases the carbon stock. We accordingly, investigated causation direction with pooled mean group estimator. Rising economic power states therefore encourage to ensure energy efficiency and replace fuel use with renewable source for heating to reduce carbon stock.

Causal relationship between agricultural production and carbon dioxide emissions in selected emerging economies.

Continuous threat posed by climate change caused by carbon dioxide emission has reignited global advocacy to confront its negative ramification with the greatest possible firmness. Global food security and agriculture face major challenges under climate change as a result of the potential negative effect of production and implementation of sectoral action to limit global warming. Overall, agricultural greenhouse emissions continue to rise and the analysis of superior data on emissions from farming, livestock, and fisheries can help countries identify opportunities to contemporaneously reduce emissions and address their food security. This study seeks to contribute to the recent literature by examining the causal relationship between agriculture production and carbon dioxide emissions in selected emerging economies for the period 1971 to 2013. The study, therefore, disaggregated agriculture production into crop production index and livestock production index to explicate the distinct and to find individual variable contribution to carbon dioxide emissions. By using FMOLS and DOLS, empirical results indicate that 1% increase in economic growth, crop production index, and livestock production index will cause a proportional increase in carbon dioxide emission by 17%, 28%, and 28% correspondingly, while 1% increase in energy consumption and population improves the environment of emerging economies. The direction of causality among the variables was, accordingly, examined using PMG estimator. Potentially, for emerging countries to achieve Sustainable Development Goal of ensuring zero hunger for their citizenry requires the need to alter their farming production techniques and also adopt agricultural technology method, which is more environmentally friendly.

A study on the causal effect of urban population growth and international trade on environmental pollution: evidence from China.

This study seeks to contribute to the recent literature by empirically investigating the causal effect of urban population growth and international trade on environmental pollution of China, for the period 1980-2014. The Johansen cointegration confirmed a long-run cointegration association among the utilised variables for the case of China. The direction of causality among the variables was, consequently, investigated using the recent bootstrapped Granger causality test. This bootstrapped Granger causality approach is preferred as it provides robust and accurate critical values for statistical inferences. The findings from the causality analysis revealed the existence of a bi-directional causality between import and urban population. The three most paramount variables that explain the environmental pollution in China, according to the impulse response function, are imports, urbanisation and energy consumption. Our study further established the presence of an N-shaped environmental Kuznets curve relationship between economic growth and environmental pollution of China. Hence, our study recommends that China should adhere to stricter environmental regulations in international trade, as well as enforce policies that promote energy efficiency in the urban residential and commercial sector, in the quest to mitigate environmental pollution issues as the economy advances.

Performance Assessment of the Juaboso District Office of the National Health Insurance Authority.

OBJECTIVES: To assess the performance of the National Health Insurance Authority (NHIA) in Ghana. METHODS: Using a thorough case study of the Juaboso District Office of the NHIA, this study assessed the community coverage rate, the annual expenditure and income, and the trend of claims payment for the period 2009 to 2012 as well as factors influencing the level of patronage of the National Health Insurance Scheme. A self-administered structured questionnaire was used to gather data from the management of the scheme. Secondary data were also gathered from the scheme's audited financial statements. Informal discussions were held with the premium collectors and clients to throw more light on revenue generation challenges. RESULTS: The study found an increasing trend in the coverage rate on a yearly basis. Over the study period, the rate moved from 30.6 to 60.1, representing an increase of 96.7%. This shows that in terms of coverage rate, the Juaboso District Office of the NHIA is performing very well. The study also found that revenue has increased but the percentage rate of increase has decreased, compared with the coverage percentage rate. Expenditure has been on the rise, increasing by as much as 20.7% in 2011. Again, the study revealed a consistent year-on-year increase in the claims payment, consistent with the national trend. CONCLUSIONS: Constant clinical auditing of claims payments is required to ensure accountability. This would lead to transparency with regard to performance assessment of the claims. The findings have important implications for the effective management of the NHIA.

Identification of small molecules that selectively inhibit diacylglycerol lipase-α activity.

Recent genetic evidence suggests that the diacylglycerol lipase (DAGL-α) isoform is the major biosynthetic enzyme for the most abundant endocannabinoid, 2-arachidonoyl-glycerol (2-AG), in the central nervous system. Revelation of its essential role in regulating retrograde synaptic plasticity and adult neurogenesis has made it an attractive therapeutic target. Therefore, it has become apparent that selective inhibition of DAGL-α enzyme activity with a small molecule could be a strategy for the development of novel therapies for the treatment of disease indications such as depression, anxiety, pain, and cognition. In this report, the authors present the identification of small-molecule inhibitor chemotypes of DAGL-α, which were selective (≥10-fold) against two other lipases, pancreatic lipase and monoacylglycerol lipase, via high-throughput screening of a diverse compound collection. Seven chemotypes of interest from a list of 185 structural clusters, which included 132 singletons, were initially selected for evaluation and characterization. Selection was based on potency, selectivity, and chemical tractability. One of the chemotypes, the glycine sulfonamide series, was prioritized as an initial lead for further medicinal chemistry optimization.

Small molecule receptor protein tyrosine phosphatase γ (RPTPγ) ligands that inhibit phosphatase activity via perturbation of the tryptophan-proline-aspartate (WPD) loop.

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan-proline-aspartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an "open" conformation or a "closed" conformation. In the current work, X-ray structures of the catalytic domain of receptor-like protein tyrosine phosphatase γ (RPTPγ) revealed a ligand-induced "superopen" conformation not previously reported for PTPs. In the superopen conformation, the ligand acts as an apparent competitive inhibitor and binds in a small hydrophobic pocket adjacent to, but distinct from, the active site. In the open and closed WPD-loop conformations of RPTPγ, the side chain of Trp1026 partially occupies this pocket. In the superopen conformation, Trp1026 is displaced allowing a 3,4-dichlorobenzyl substituent to occupy this site. The bound ligand prevents closure of the WPD-loop over the active site and disrupts the catalytic cycle of the enzyme.

A high-throughput screen for receptor protein tyrosine phosphatase-gamma selective inhibitors.

Protein tyrosine phosphatase-γ (PTP-γ) is a receptor-like PTP whose biological function is poorly understood. A recent mouse PTP-γ genetic deletion model associated the loss of PTP-γ gene expression with a potential antidepressant phenotype. This led the authors to screen a subset of the Bristol-Myers Squibb (BMS) compound collection to identify selective small-molecule inhibitors of receptor-like PTP-γ (RPTP-γ) for use in evaluating enzyme function in vivo. Here, they report the design of a high-throughput fluorescence resonance energy transfer (FRET) assay based on the Z'-LYTE technology to screen for inhibitors of RPTP-γ. A subset of the BMS diverse compound collection was screened and several compounds identified as RPTP-γ inhibitors in the assay. After chemical triage and clustering, compounds were assessed for potency and selectivity by IC(50) determination with RPTP-γ and two other phosphatases, PTP-1B and CD45. One hundred twenty-nine RPTP-γ selective (defined as IC(50) value greater than 5- to 10-fold over PTP-1B and CD45) inhibitors were identified and prioritized for evaluation. One of these hits, 3-(3, 4-dichlorobenzylthio) thiophene-2-carboxylic acid, was the primary chemotype for the initiation of a medicinal chemistry program.

2-Arylbenzoxazoles as novel cholesteryl ester transfer protein inhibitors: optimization via array synthesis.

2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described.