Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain

Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.     

Applying Leontief's Price Model to Estimate Missing Elements in Hybrid Life Cycle Inventories

This article presents an approach to estimate missing elements in hybrid life cycle inventories. Its development is motivated by a desire to rationalize inventory compilation while maintaining the quality of the data. The approach builds on a hybrid framework, that is, a combination of process‐ and input–output‐based life cycle assessment (LCA) methodology. The application of Leontief's price model is central in the proposed procedure. Through the application of this approach, an inventory with no cutoff with respect to costs can be obtained. The formal framework is presented and discussed. A numerical example is provided in Supplementary Appendix S1 on the Web.     

Integrated Environmental and Economic Assessment of Products and Processes

The eco-efficiency analysis method developed and used by the Öko-Institut analyzes different alternatives that fulfill a defined consumer need, from an environmental as well as an economic perspective.
Like life-cycle assessment (LCA), eco-efficiency analysis makes possible the setting of priorities in purchasing decisions or can be used to show optimization potentials in product development processes.
Eco-efficiency analysis builds upon two methods: LCA, according to ISO 14040 ff. (to assess the environmental aspects of products and processes), and life-cycle costing. Life-cycle costing results in a single figure—the total costs of ownership to one or several actors. The environmental impacts can be evaluated and aggregated as a single score or the impact category indicator results can be kept separate. In either case two single scores can be compared: the total environmental burden or the impact category indicator results, and the total costs of ownership of the alternatives under consideration.
The results can then be plotted in two-dimensional graphs that show the effectiveness of certain measures in environmental and economic terms. The efficiency is expressed as a numerical ratio of environmental savings to difference in costs.
Together with furnishing more detailed results and a discussion of additional benefits or potential barriers, eco-efficiency analysis broadens the basis for decision-making processes.     

Extended Producer Responsibility for Waste Electronics: An Example of Printer Recycling in the United Kingdom

In February 2003, European Union (EU) policy makers implemented a Directive that will make producers responsible for waste electrical and electronic equipment at end-of-life (known as the "WEEE" Directive). Under this new legislation, producers are required to organize and finance the take-back, treatment, and recycling of WEEE and achieve mass-based recycling and recovery targets. This legislation is part of a growing trend of extended producer responsibility for waste, which has the potential to shift the world's economies toward more circular patterns of resource use and recycling. This study uses life-cycle assessment and costing to investigate the possible environmental effects of the WEEE Directive, based on an example of printer recycling in the United Kingdom.
For a total of four waste management scenarios and nine environmental impact categories investigated in this study, results varied, with no scenario emerging as best or worst overall compared to landfilling. The level of environmental impact depended on the type of material and waste management processes involved. Additionally, under the broad mass-based targets of the WEEE Directive, the pattern of relationships between recycling rates, environmental impacts, and treatment and recycling costs may lead to unplanned and unwanted results. Contrary to original EU assumptions, the use of mass-based targets may not ensure that producers adapt the design of their products as intended under producer responsibility.
It is concluded that the EU should revise the scope of consideration of the WEEE Directive to ensure its life-cycle impacts are addressed. In particular, specific environmental objectives and operating standards for treatment and recycling processes should be investigated as an alternative to mass-based recycling and recovery targets.     

Incorporating costs in LCA

The goal of LCA is to identify the environmental impacts resulting from a product, process, or activity. While LCA is useful for evaluating environmental attributes, it stops short of providing information that business managers routinely utilize for decision-making — i.e., dollars. Thus, decisions regarding the processes used for manufacturing products and the materials comprising those products can be enhanced by weaving cost and environmental information into the decision-making process. Various approaches have been used during the past decade to supplement environmental information with cost information. One of these tools is environmental accounting, the identification, analysis, reporting, and use of environmental information, including environmental cost data. Environmental cost accounting provides information necessary for identifying the true costs of products and processes and for evaluating opportunities to minimize those costs. As demonstrated through two case studies, many companies are incorporating environmental cost information into their accounting systems to prioritize investments in new technologies and products.     

The Effect of Life Cycle Cost Information on Consumer Investment Decisions Regarding Eco-Innovation

Life cycle cost (LCC) computations are a well-established instrument for the evaluation of intertemporal choices in organizations, but they have not been widely adopted by private consumers yet. Consumer investment decisions for products and services with higher initial costs and lower operating costs are potentially subject to numerous cognitive biases, such as present-biased preferences or framing effects. This article suggests a classification for categorizing different cost profiles for eco-innovation and a conceptual model for the influence of LCC information on consumer decisions regarding eco-innovation. It derives hypotheses on the decision-making process for eco-innovation from a theoretical perspective. To verify the hypotheses, the publication reviews empirical studies evaluating the effects of LCC information on consumer investment decisions. It can be concluded that rather than finding ways to make customers pay more for environmentally sound products, the marketing challenge for eco-innovation should be reconceptualized as one of lowering customers' perceived initial cost and increasing awareness of LCC. Most existing studies report a positive effect of LCC information on the purchase likelihood of eco-innovations. Disclosing LCC information provides an important base for long-term thinking on the individual, corporate, and policy levels.     

Advances in Proteomics in Cancer Research

Proteases are a family of proteolytically active enzymes whose dysfunction is implicated in a wide variety of human diseases. Although an estimated 2% of the human genome encodes for proteases, only a small fraction of these enzymes have well-characterized functions. Identification of the specificity and natural substrates of proteases in complex biological samples is challenging, but proteomic screens for proteases are currently experiencing impressive progress. Such proteomic screens include peptide-based libraries, fluorescent 2D difference gel electrophoresis with mass spectrometry, differential isotope labeling in combination with mass spectrometry, quantitative degradomics analysis of proteolytically generated neo-N-termini, and activity-based protein profiling. In the present article, we summarize and discuss the current status of proteomic techniques to identify protease specificity, cleavage sites and natural substrates with a particular focus on the cytotoxic lymphocyte granule serine proteases granzymes.     

Using BEES to select cost-effective green products

The BEES (Building for Environmental and Economic Sustainability) software brings to your fingertips a powerful technique for balancing the environmental and economic performance of building products. The tool is based on consensus standards and designed to be practical, flexible, and transparent. Version 2.0 of the Windows™-based decision support software, aimed at designers, builders, and product manufacturers, includes actual environmental and economic performance data for 65 building products. The purpose is to support purchasing decisions by providing key science-based information often lacking in ‘green’ product selection. The intended result is a cost-effective reduction in building-related contributions to environmental problems. Contribution of the National Institute of Standards and Technology (NIST) and not subject to copyright in the United States. NIST does not endorse any particular brand, product, or service.