Merck & Co Inc
12 Projects, page 1 of 3
- Project . 2008 - 2009Funder: UKRI Project Code: BB/F010850/1Funder Contribution: 93,387 GBPPartners: Merck & Co Inc, University of Bath
Analysis of molecular and cellular events is crucial in modern life sciences research, for a better understanding of (i) fundamental biological processes, (ii) the changes that characterise associated disease states, and (iii) the development of therapeutics. This research proposal brings together seven research areas, spanning the regulation of the immune and nervous systems, haemopoiesis, tissue development and regeneration and cell metabolism that share a common theme of wanting to utilise sensitive, quantitative and high throughput state-of-the-art instrumentation to analyse a range of cellular mechanisms. This instrument is the Mesoscale Discovery (MSD) SECTOR Imager (SI) 6000 which offers a sensitive, adaptable platform with which to measure several analytes in cell or cell-derived samples. The technology relies on the use of chemically tagged antibodies that recognize the analytes of choice. When bound to their target, the Abs emit light upon electrochemical stimulation which is measured and quantified. The main features provided by the instrument are: - the ability to accurately quantify activation of specific signals; - it facilitates detection of multiple signals simultaneously. - in situations where cell samples may be limiting, information on several different signalling molecules can be generated simultaneously. - the system allows for more rapid analysis, - provides platform for developing our own custom made assays for future applications.
- Project . 2016 - 2019Funder: UKRI Project Code: EP/N031792/1Funder Contribution: 642,774 GBPPartners: Astrazeneca Plc, University of Cambridge, Merck & Co Inc
Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in a large number of pharmaceutical agents. The groups appended to these nitrogen atoms are crucial in determining the physical properties of the amine and are linked to how well it interacts with a biological target. Despite the apparent simplicity of the aliphatic amine motif, the number of general methods available for the synthesis of this important feature is surprisingly small. Methods such as reductive amination, alkylative tactics, hydroamination and transamination have met the demand for many years, however the development of new straightforward methods for the synthesis of complex systems is essential for the continued advance of synthesis. A systematic method for the synthesis of complex aliphatic amines would be valuable to practitioners of drug discovery, and a streamlined approach to these molecules could involve a catalytic process capable of transforming simple, readily available aliphatic amines into complex variants via selective functionalization of their C-H bonds. Methods that enable the practical and selective functionalization of inert aliphatic C-H bonds have applications in fields that range from fine chemical production to drug discovery. Transition metal catalysis has emerged as a powerful tool to activate these traditionally unreactive C-H bonds. Several classes of functional group can direct C-H activation via a process called cyclometallation; coordination of the metal centre to a proximal Lewis basic atom steers the catalyst into position where the C-H bond can be cleaved. Reaction of the resulting C-metal bond with an external reagent leads to an overall transformation that sees a C-H bond converted into a versatile motif. Cyclometallation has led to a number of useful catalytic C-H functionalization processes that have expanded the chemists toolbox of available reactions; tailoring the electronic properties of directing functionalities has enabled cyclometallation in aliphatic hydrocarbons displaying carboxylic acid, hydroxyl groups, and derivatives of these motifs. Despite these advances, related transformations on aliphatic amines are rare and successful examples require the use of strongly electron withdrawing sulfonyl or bespoke directing groups to modulate the metal coordinating power of the nitrogen atom. As such, their synthetic intractability frequently precludes the wider application of strategic C-H bond activation in aliphatic amine systems. The overarching aim of this proposal is to establish aliphatic amines as viable feedstock molecules for C-H activation using a novel activation strategy. This will provide distinct C-H disconnections that will form part of a C-H activation road map for synthesis. The aliphatic amine motif is so ubiquitous in pharmaceutically relevant molecules that it is considered a 'privileged' feature and so we will investigate how the multi-faceted C-H activation platform can be translated into viable applications that have impact drug discovery and development.
- Project . 2015 - 2017Funder: UKRI Project Code: BB/M021947/1Funder Contribution: 199,584 GBPPartners: University of Greifswald, Merck & Co Inc, ALMAC SCIENCES, NTU
Chiral amines are prevalent in natural products, which often display potent biological activity. Such chiral amine motifs are also frequently found in pharmaceutical drug compounds and chemical building blocks meaning that the development of environmentally benign and sustainable routes to produce these important motifs is extremely desirable. Nature synthesizes these complex and valuable molecules through the action of highly specialized enzymes. These natural catalysts enable an extremely efficient biosynthesis from simple starting materials, installing functional groups with exceptional levels of selectivity. Chemical catalysts are frequently designed to mimic the action of enzymes and are often capable of achieving impressive selectivity. However, unlike enzymes, processes involving these catalysts usually involve high temperatures, sub-optimal pH, organic solvent and complex purification methods. Enzymes called omega-transaminases (TAs) catalyze the conversion of commercially available or easily accessible starting materials to high-value amines. These biocatalysts require an additional donor molecule to provide the amine functional group. This donor is ultimately converted to a by-product and the desired amine product is formed. However, the reaction is freely reversible and unless this by-product is removed from the reaction, low yields of the desired amine will be isolated, as the enzyme will more readily catalyse the reverse reaction to regenerate starting materials. A number of elegant approaches have been reported which remove this ketone by-product and allow access to appreciable quantities of the chiral amine. These strategies include the addition of expensive enzymes or the use of extremely large quantities of the amine donor in combination with the technically challenging removal of ketone by-products. One such approach, which relies on an extensively modified TA, is currently used for the industrial synthesis of the antidiabetic drug compound, sitagliptin. However, the approach is far from efficient and the development of this heavily modified TA biocatalyst was enormously challenging, highlighting an immediate need for more sustainable strategies for performing these biotransformations and for developing suitable enzyme catalysts. This research will build upon recent work reported in our laboratory that describes arguably the most efficient approach to date for performing biotransformations involving TAs. The success of the approach is due to spontaneous precipitation of the by-product, which cannot regenerate starting materials. This polymer is also highly colored and has allowed the development of an effective high-throughput screening strategy that enables the rapid identification of active enzymes. Our focus now is to optimize the process further and make it more suitable for industrial application. Specifically, low cost amine donor molecules will be used that are spontaneously removed from the reaction in a similar way to our previously reported method. We will also apply a simple high-throughput screening strategy to assist in the genetic engineering of natural enzymes in order to increase the scope of the reactions that they can catalyze and make them suitable for industrial scale synthesis. The enzymes developed in this study will enable cost-effective, sustainable and environmentally neutral methods for the small/medium and industrial scale production of one of the most important compound classes.
- Project . 2015 - 2016Funder: UKRI Project Code: BB/N00390X/1Funder Contribution: 5,400 GBPPartners: McMaster University, Merck & Co Inc, NOVARTIS, UQ, University of Warwick
- Project . 2016 - 2021Funder: UKRI Project Code: EP/N025245/1Funder Contribution: 2,270,300 GBPPartners: AkzoNobel UK, Nestle SA, Bristol-Myers Squibb Pharmaceutical Rese, Syngenta Ltd, Hovione (International), Kuecept Ltd, Durham University, Inca Digital Printers (United Kingdom), CPI, Chief Ai Limited...
'Watching paint dry' is a metaphor for a boring and pointless activity. In reality, the drying of liquids is a complex process and the imperturbable appearance to the eye can hide a wealth of dynamics occurring inside the liquid. The effect of these internal processes is to change the distribution of materials in the deposit left after drying. We are all familiar with the coffee-ring effect, where split coffee dries to form a ring of solids at the edge of the spill - of little use if you are trying to coat a surface uniformly. This project is all about the drying of droplets, either in air or on a surface; one isolated droplet, two droplets merging or many droplets in a spray. We seek to understand how drops dry and how to control where the particles or molecules in the drop end up after the drop evaporates. When do you get a solid particle or a hollow particle? A round one or a spiky one? A uniform particle or one with shells? Or on a surface: a coffee-ring or a pancake? A uniform deposit, a layered one or a bull's eye? Are particles crystalline or amorphous, are different components mixed or separated? There are a myriad of possibilities for controlling the microstructure and properties of the final particle or film. Drying is complicated for three main reasons. First, many transport processes (evaporation, heat flow, diffusion, convection) occur simultaneously and are strongly coupled. For example, in a small droplet of alcohol and water evaporating on a surface, the liquid inside the drop will flow around in a doughnut pattern tens of times each second. Second, the conditions in a drying droplet are often far from equilibrium. For example, a small water droplet in air or on a smooth clean surface can be cooled to -35 degrees C without freezing. So to understand drying one needs to understand the properties of fluids far from equilibrium. It is generally not possible to predict the final outcome of drying from the properties of simple solutions near equilibrium. Third, drops do not dry in isolation. They may merge or bounce, coalesce or chase each other across a surface. The evaporation of one droplet affects its neighbours. Moving droplets change the flow of air around other droplets, coupling the motion of droplets. Why does anyone care, beyond the intellectual fascination with the bizarre outcomes of droplet drying? Drying of droplets turns out to be a rather important process in practical applications: spray painting, graphics printing, inkjet manufacturing, crop spraying, coating of seeds or tablets, spray cooling, spray drying (widely used in food, pharmaceutical and personal care products), drug inhalers and disinfection, to give a few examples. The physics and chemistry underlying all these applications is the same, but if manifests itself in different ways and the desired outcome varies between applications. The first challenge addressed by this project is one of measurement: how do you work out what is going on in a droplet that is less than a tenth of a millimetre across and may dry in less than a second? We have already developed sophisticated measurement tools but will need to extend these further. Another challenge is one of modelling: to understand the drying process we need a theoretical framework and computer models to explain - and predict - experimental observations. We will begin looking at the fundamental processes occurring in single drops in air and on a surface and then explore what happens when drops interact or coalesce. This fundamental understanding will be fed into improved models of arrays, clouds or sprays of droplets that are encountered in most practical applications (such as spray coating, spray drying, inhalers or inkjet manufacturing). We will use an Industry Club to engage with companies from a range of different sectors. This Club will provide a forum for sharing problems, ideas and solutions and for disseminating the knowledge generated in the project.