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Hogberg T.,Chemical Research | Frimurer T.M.,Copenhagen University | Sasmal P.K.,Dr. Reddys Laboratories Ltd
Bioorganic and Medicinal Chemistry Letters | Year: 2012

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of ∼2000 diverse MCHR1 and ∼1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design. © 2012 Elsevier Ltd. All rights reserved.

Scott J. Miller, Irénée du Pont Professor of Chemistry at Yale University, has been named the new editor-in-chief of the ACS peer-reviewed publication, the Journal of Organic Chemistry, which focuses on the theory and practice of organic chemistry. Miller will succeed Dale Poulter, who has led the journal since 2001 and substantially expanded the scope of the publication to include perspectives, synopses, and special issues. Miller will begin his appointment on Jan. 1. “Scott is an outstanding organic chemist” says Poulter. “He’s widely known in the community, he has a major research program, he publishes absolutely outstanding work, he’s very visible in the community, and he’s energetic and enthusiastic.” “Dr. Miller’s ability to engage and inspire researchers, his impressive scholarship and unparalleled passion for organic chemistry, and his prior experience as a senior editor at Accounts of Chemical Research will ensure JOC remains at the forefront of the field,” says James Milne, senior vice president of ACS Journals Publishing Group. Miller’s research focuses on the development of chemical synthesis using the architecture and design principles offered by biologically relevant structures and professes to seek to discover new reactions and apply new principles to the selective synthesis of complex molecules. “I’m very excited to contribute to a field that I feel so passionate about and that I find so fascinating,” Miller says. “One of the triumphs of organic chemistry has been its impact on a lot of interdisciplinary sciences, but at the same time, I think that some of the excitement in the interdisciplinary impact creates new opportunities to explore the fundamentals.” He says he also plans on highlighting the interdisciplinary work at the crossroads between industry and academia. Miller praised Poulter for his contributions to the journal. “He has done an outstanding job making the Journal of Organic chemistry a great place for really deep scholarship in the field,” Miller says.

News Article | September 9, 2016
Site: www.rdmag.com

Several professionals in the scientific world have increasingly acknowledged that in assessing the toxicity of chemicals, drugs and consumer products, animal use should be minimized and, where possible, data should be acquired using alternative in vitro based methodologies. This is part of the widely-recognized set of principles known as the ‘3Rs’ of scientific animal research: One of the goals of ‘21st Century Toxicology’, as set-out in the U.S. National Research Council’s landmark Vision and Strategy report, is to replace in vivo testing methodologies with in vitro procedures on human cells, followed by computational systems biology modelling to determine toxicological risk. The U.S. Food and Drug Administration has identified ‘modernizing toxicology’ as one of its priority areas and has furthermore explicitly expressed an interest in learning about new toxicity testing procedures that could help it meet these goals. As part of the ongoing assessment of Reduced-Risk Products (RRPs), products with the potential to reduce individual risk and population harm in comparison to cigarettes, Philip Morris International (PMI) has recently published two papers that demonstrate the potential of novel in vitro-based testing procedures to help realize the vision of 21st Century Toxicology. The RRP investigated is the Tobacco Heating System 2.2 (THS), a new technology that heats tobacco without burning it, thereby reducing or eliminating the formation of many of the harmful compounds that are produced by cigarettes. One study looked at the biological impact of THS aerosol on the oral epithelium, the other on the nasal epithelium. A third study is currently underway to assess the biological impact of THS aerosol on bronchial epithelial cells. The studies, published in the journals Chemical Research in Toxicology and ALTEX, used human cells grown in three-dimensional culture systems. The cultures were grown on top of an artificial membrane at the air-liquid interface, allowing them to develop ‘organotypic’ tissue complexity closely resembling that found in the human oral cavity and airways, respectively. Cultures were then exposed to either THS aerosol or cigarette smoke at various concentrations with comparable nicotine concentrations. The biological impact of exposure was assessed at time-points between four and 72 hours using a combination of well-established in vitro testing procedures and novel computational techniques. Multiple endpoints were analyzed. These included measurements of cytotoxicity, alterations in tissue morphology (histology), impact on processes involved in the metabolism of toxicants (xenobiotic metabolism response), secretion of pro-inflammatory mediators, and perturbation of genome-wide gene profiles. The nasal study also looked at ciliary function. The adopted computational techniques involved the processing of collected data through a set of literature-supported biological network models that are known to relate to respiratory disease, e.g., oxidative stress, osmotic stress and hypoxic stress (a total of 28 network models were used in the oral study, 29 in the nasal study). The biological impact of cigarette smoke and THS aerosol was then quantified through the assignment of Network Perturbation Amplitude (NPA) scores, and complemented by standard gene-set analysis. Multiple experimental repetitions were conducted (five in the nasal study, four in the oral study) in order to obtain robust, reliable and reproducible measurements. Taken together, the results of the two studies demonstrate that the biological impact of THS aerosol is predominantly non-significantly different from the air control exposure, and much reduced when compared with the impact of cigarette-smoke exposure. It was possible to induce findings of toxicity with THS, but only at significantly higher exposure concentrations of the aerosol than conventional cigarette smoke. There were also no additional or new findings of toxicity following THS aerosol exposure when compared with the toxicity elicited following cigarette smoke exposure. The studies have demonstrated not just the risk-reduction potential of THS in comparison with cigarettes, but also the ability to generate comprehensive and meaningful insights using human cell-based in vitro systems in combination with computational assessment strategies. The studies should be of interest to all scientists who are keen to further minimize the use of animals in the development of 21st Century Toxicology. They further have important implications for industries such as pharmaceuticals and biotechnology, as well as for regulatory bodies responsible for the scientific oversight of chemicals, drugs and a range of consumer products. Julia Hoeng is the director of Systems Toxicology, Biological Systems Research at Philip Morris International. Anita Iskandar is a scientist at Philip Morris International. Filippo Zanetti is a scientist at Philip Morris International.

Liang X.,Chemical Research | Grue-Sorensen G.,Chemical Research | Petersen A.K.,API Development | Hogberg T.,Chemical Research
Synlett | Year: 2012

A high-yielding method was developed for the preparation of ingenol 3-angelate (PEP005, ingenol mebutate) via the corresponding 5,20-acetonide without concomitant isomerization of the angelate (Z-form) to the corresponding tiglate (E-form). The general scope of the stereoconservative esterification method was further evaluated on several different alcohols, giving the angelates in up to quantitative yield without isomerization to the tiglate. © Georg Thieme Verlag KG Stuttgart · New York.

Grue-Sorensen G.,Chemical Research | Liang X.,Chemical Research | Mansson K.,Chemical Research | Vedso P.,Chemical Research | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKCδ activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKCδ for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKCδ. © 2013 Elsevier Ltd. All rights reserved.

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