
Pfizer Global R and D
Pfizer Global R and D
59 Projects, page 1 of 12
assignment_turned_in Project2024 - 2027Partners:Imperial College London, Pfizer Global R and DImperial College London,Pfizer Global R and DFunder: UK Research and Innovation Project Code: EP/Y007859/1Funder Contribution: 525,229 GBPMore efficacious and better-tolerated drugs are crucial for the treatment of serious and common medical conditions. Scientists involved in discovering drug compounds require synthetic methods that allow them to design molecules with optimal properties. The development of new methods will also influence the design of such compounds by providing new structural motifs as design options, and by providing new ways to connect and functionalise molecules. Small rings (examples include oxetanes and azetidines) are highly attractive in drug discovery, but are vastly understudied, not least through lack of suitable preparative methods. This prevents their exploitation. The incorporation of these rings can lead to improved properties in a drug molecule. Furthermore, they can be envisaged as replacements for other more common structures that can fine-tune and improve the properties of a compound (the idea of being a 'bioisostere'). This research will harness these ring structures in novel, stable and easily handled reagents that can be prompted to react in a new type of coupling process that generates a reactive intermediate under mild conditions. The new reagents allow the generation of collections of valuable compound collections and the 'late-stage' functionalisation complex drug candidates and biological molecules to improve and tailor their molecular properties. The research consists of 3 parts. The first will prepare new reagents and establish their reactivity and synthetic characteristics. These will be used to prepare new molecules that will be valuable for testing in drug discovery, for example in fragment based drug discovery, a strength of UK industry. Analogues of current drug molecules will also be prepared replacing key features with the new small rings as bioisosteres. Part 2 will compare the properties of some of the new types of molecules prepared with those containing different more common groups to establish the change in properties. This will inform synthetic and medicinal chemists on when to exploit the new designs in drug design. Derivatives that will be prepared in this work present a exciting potential as bioisosteres for amides, perhaps the most common functional group in drug compounds. Finally, the new reagents will be examined in peptide functionalisation using water tolerant derivatives and to establish selectivity. These fundamental studies will lead to new types of probes to investigate biological systems. Each stage will develop new synthetic chemistry and reactivity features, and provide new insights for medicinal chemists.
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For further information contact us at helpdesk@openaire.euassignment_turned_in Project2011 - 2012Partners:University of Leeds, Malvern Inst, Pfizer Global R and D, The University of Manchester, University of Leeds +20 partnersUniversity of Leeds,Malvern Inst,Pfizer Global R and D,The University of Manchester,University of Leeds,CCDC,NNL,University of Salford,NNL,Infineum UK,Pfizer (United Kingdom),National Nuclear Laboratory (NNL),Pfizer Global R and D,Syngenta (United Kingdom),Cambridge Crystallographic Data Centre,Syngenta Ltd,Malvern Instruments Ltd,Syngenta Ltd,Spectris (United Kingdom),Malvern Panalytical Ltd,Infineum UK,Pfizer Global R and D,University of Manchester,CCDC,Infineum (United Kingdom)Funder: UK Research and Innovation Project Code: EP/I028293/1Funder Contribution: 196,531 GBPThis proposal seeks EPSRC Follow-On grant funding to fund the technical and commercial development and integration of molecular modelling software (HABIT and SYSTSEARCH) developed by the crystallisation science and engineering research group at the University of Leeds which enables the prediction of the crystal shape and related surface chemistry of pharmaceutical, fine chemical and energy solid phase products and their mediation by their crystallisation environment. The predictive approach developed draws down on the modelled material's crystallographic structure together with the application of appropriate empirical inter-atomic/molecular force-field parameters through which the structure's key inter-molecular interactions (supra-molecular synthons) for both host (homo-synthons) and growth environment (hetero-synthons related to e.g. solvent, additives and impurities) can be identified, characterised regarding their strength and directivity and related to the product's physical and chemical properties. The work has been developed through a previous EPSRC senior fellowship programme and a number or associated EPSRC research grants. Commercialisation is envisaged through re-engineering the software based on user requirements, afforded through the data-bases and software of the Cambridge Crystallographic Data Centre (CCDC) and, through this, providing a significant enhancement of the predictive resources available to both academic and industrial research groups. The commercially robust software package, HABIT2011, will be offered through CCDC and directly to end user customers. The Synthonic Engineering identity will be established as an internal project, initially internally incubated within the University and later established as a spin off company. Synthonic Engineering will support the continuing technical and scientific development/enhancement of the HABIT2011 software; facilitate product licensing opportunities for other potential users; and provide consultancy, know-how and contract research support to the commercial sector. The utility of the modelling will be embedded within 4 key representative end-user companies: pharmaceuticals (Pfizer), agrochemicals (Syngenta), fuels (Infineum) and nuclear processing (National Nuclear Laboratory) through applications demonstrators on commercial compounds and at least one scientific instrument company (Malvern Instruments). These companies will also provide membership for a steering board to ensure the project's currency to the industrial sector.
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For further information contact us at helpdesk@openaire.euassignment_turned_in Project2011 - 2015Partners:UCL, Pfizer Global R and D, Pfizer (United Kingdom), Pfizer Global R and D, Pfizer Global R and DUCL,Pfizer Global R and D,Pfizer (United Kingdom),Pfizer Global R and D,Pfizer Global R and DFunder: UK Research and Innovation Project Code: BB/I016635/1Funder Contribution: 99,932 GBPTo understand how receptors are targeted to specific inhibitory synapses in the brain, we need to study the 'life cycle' of native receptors on the surface membrane. GABA-A receptors are inserted and undergo constitutive endocytosis and some recycling back to the surface(1,2), which affects the efficacy of synaptic inhibition(1,3). By using a reporter mutation in the GABA ion channel, we demonstrated for the first time that synaptic GABA-A receptors are rapidly mobile on the surface membrane(4) allowing an exchange with extrasynaptic receptors(5). Although the mobility of synaptic/extrasynaptic receptors can be investigated with increased resolution, these methods require the expression of mutant receptor subunits in neurones. To track the movement of native receptors requires the development of highly-selective ligands that can covalently bind to the receptor and affect its function, so that the movement of receptors can be followed using electrophysiological methods. To investigate native GABAA receptor mobility at synapses, we will design and synthesise photoaffinity labelled antagonists that upon irradiation will bind irreversibly to the receptor causing inhibition. We have chosen gabazine as our template molecule since this inhibitor is specific for GABA-A receptors, has high affinity, and as it has been shown that structural variation on the biaryl core is well tolerated(6). We will synthesise photoaffinity labelled gabazine analogues, varying the nature and position of the photoaffinity label. To achieve this we will use a highly efficient 4-step synthesis employing palladium cross-coupling as the key step. By flash irradiation at precise surface membrane locations in the presence of our gabazine analogues, we will inactivate discrete populations of GABA-A receptors (extrasynaptic and/or synaptic). By monitoring both phasic and tonic GABA currents, we will be able to track the movement of native receptors in synaptic and extrasynaptic membrane domains. Adopting this approach means we neither have to mutate the receptor to incorporate a tag nor express this in neurones; secondly, we can measure the speed of movement of receptors in defined membrane areas by monitoring the recovery of GABA currents following photoactivation. We can then distinguish between lateral mobility and exocytosis of GABA-A receptors using selective inhibitors (eg., botulinum toxins) as well as being able to estimate the mean number of functional receptors at inhibitory synapses and their relative change over time(4). Activity-based proteomic profiling has a variety of powerful applications in drug discovery and chemical biology, including sophisticated measurements of selectivity and target occupancy and biomarker development. Affinity-based proteomics extends the utility of this area, and is of significant interest within both academia and the pharmaceutical industry. Notably there remains a paucity of methods and suitable ligands for probing the proteome of ion channels, a recognised drug target. In this collaboration between UCL and Pfizer we want to develop new affinity-based probes for ion channels, to enable measurements of the functional proteome and to determine target occupancy. The GABA ion channel presents an ideal model system to develop the utility of activity-based chemical probes for proteomic profiling. 1. B. Luscher et. al., Pharmacol. Ther. 102, 195 (2004). 2. T. G. Smart et. al., Nat. Rev. Neurosci. 2, 240 (2001). 3. F. K. Bedford et. al., Nat. Neurosci. 4, 908 (2001). 4. T. G. Smart et. al., Nat. Neurosci. 8, 889 (2005). 5. T. C. Jacob et. al., J. Neurosci. 25, 10469 (2005). 6. C. G. Wermuth et. al., J Med. Chem. 30, 239 (1987).
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For further information contact us at helpdesk@openaire.euassignment_turned_in Project2009 - 2013Partners:Swansea University, Pfizer Global R and D, Pfizer (United Kingdom), Pfizer Global R and D, Swansea University +1 partnersSwansea University,Pfizer Global R and D,Pfizer (United Kingdom),Pfizer Global R and D,Swansea University,Pfizer Global R and DFunder: UK Research and Innovation Project Code: BB/G017131/1Funder Contribution: 74,410 GBPDevelopment of a vigorous mammalian embryo depends on ovulation and fertilisation of a competent oocyte from a healthy ovarian follicle. However, uterine bacterial infections or inflammation during follicle growth, oocyte maturation and early embryo development are associated with infertility. The scientific question this project addresses is: How do bacterial infections or inflammation affect oocytes and early embryos? We study cattle because bacterial infection of the uterus is ubiquitous after parturition in this species, and 40% of animals have uterine disease. We identified that cattle with uterine disease have perturbed ovarian function and low conception rates - even after 'successful' treatment. Indeed, dairy cattle have the lowest conception rate of all domestic animals and our CASE partner needs to develop new therapeutics to solve this problem. Host immunity and inflammatory responses are dependent on receptors on host cells recognising pathogen associated molecular patterns (PAMPs). We found that follicular fluid contains PAMPs, and follicle cells express the necessary immune receptors. We believe that the release of PAMPs or the inflammation associated with uterine infection, impairs oocyte maturation and embryo development. The project tests the hypothesis that ovarian follicle, oocyte and early embryo health is perturbed by PAMPs either directly or via inflammatory mediators. We will pursue 4 objectives: 1. Measure the effect of PAMPs and inflammatory mediators on oocytes and embryos in vitro Ovarian follicles, follicle cells, oocytes and IVF blastocysts will be challenged with PAMPs (LPS, LTA, flagellin) or inflammatory mediators in long-term culture, and we will evaluate: - Markers of follicle and oocyte health: steroid secretion (oestradiol, androstenedione, and progesterone), hormone receptor expression (LHR, FSHR, EGFR), and developmental genes (Mater, Zar-1, Mos, BMP15, GDF9, JY-1) - Gene expression of inflammatory mediators: TNF, IL-1, IL6, iNOS, prostaglandins - Embryo cleavage and blastocyst rates following IVF - Cytoskeleton structure of the oocyte and embryo by confocal imaging of trans-zonal projections, nuclear configuration and mitochondria 2. Determine the vulnerability of oocytes and embryos to infection and inflammation in vivo Oocytes collected for IVF and their blastocysts will be treated with a PAMP or a pro-inflammatory cytokine (identified in objective 1) before embryo transfer into normal animals, and the establishment of pregnancy will be monitored. In addition, blastocysts and early embryos will be collected from animals that had a normal postpartum period or uterine disease, and embryo development compared using IHC and gene expression. 3. Identify the cellular pathways activated in response to PAMPs and inflammation Follicle cells, oocytes and embryos will be treated with PAMPs or cytokines. The expression of immune (TLRs, NOD) and endocrine (LHR, FSHR, EGFR) receptors will be measured by qPCR or Western blotting. There appears to be considerable cross talk between the receptor signalling pathways used for reproduction and immunity. So, immune (nuclear factor-kappa B, Caspase-1 and MAPK) and endocrine (cAMP, PKA, MAPK) signalling pathways, and receptor regulators (ARF6, arrestins) will be explored using Western blotting, IP, ELISA and commercial kits. 4. Mechanistic studies to limit the effect of PAMPs and inflammation on fertility At Pfizer and the ILS, the student will test which agonists and inhibitors of cellular pathways limit the detrimental effect of PAMPs or cytokines on the vulnerable stages of oocyte and embryo development. By the end of the studentship we will have answered fundamental questions about how infection, immunity and inflammation affect reproduction. Knowledge of these mechanisms will be exploited by the Pfizer bovine reproduction international research network to select drug targets of clinical relevance for future in-vivo studies.
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For further information contact us at helpdesk@openaire.euassignment_turned_in Project2009 - 2012Partners:University of Oxford, Pfizer Global R and D, Pfizer (United Kingdom), Pfizer Global R and D, Pfizer Global R and DUniversity of Oxford,Pfizer Global R and D,Pfizer (United Kingdom),Pfizer Global R and D,Pfizer Global R and DFunder: UK Research and Innovation Project Code: EP/G027838/1Funder Contribution: 163,345 GBPMicrofluidics provides an exceptional environment for the generation of controlled droplet dispersions and their manipulation in prescribed flow fields. The spatio-temporal correspondence between microchannel position and reaction 'time' permits the study of kinetics of (chemical and physical) processes with unprecedented time resolution and dynamic range. Further, the combination of the small volumes of droplet 'reactors' and the precise formulation of their composition opens vast possibilities in chemical synthesis, including screening, discovery and optimisation. Monitoring reactions in real-time with non-invasive probes remains, hitherto, a major shortcoming of microchemical reactors due to the minute sample volumes (pL-nL) and fast travel speeds (1-1000 mm/s). This proposal seeks to develop, implement and validate a novel experimental approach to monitor microchemical reactions in real-time by coupling, for the first time, cavity ring-down spectroscopy and solvent-resistant microfabrication. This approach will permit the online study of model catalytic reactions, with unprecedented reproducibility and flow control. Cavity ring-down spectroscopy will permit the analysis of pL volumes, effectively eliminating the restriction of path length in microchannels, with nanosecond to microsecond time resolution, compatible with microreaction drops. In particular, we will elucidate individual and global reaction population outcomes and the effect of mixing and flow, with spatiotemporal resolution. This approach is applicable to a range of organic chemical reactions and, for this work, we will focus on selected model systems (detailed below) of fundamental and industrial relevance.
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