Medicines Research Center

Stevenage, United Kingdom

Medicines Research Center

Stevenage, United Kingdom
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Docherty J.H.,University of Edinburgh | Peng J.,University of Edinburgh | Dominey A.P.,Medicines Research Center | Thomas S.P.,University of Edinburgh
Nature Chemistry | Year: 2017

First-row, earth-abundant metals offer an inexpensive and sustainable alternative to precious-metal catalysts. As such, iron and cobalt catalysts have garnered interest as replacements for alkene and alkyne hydrofunctionalization reactions. However, these have required the use of air- and moisture-sensitive catalysts and reagents, limiting both adoption by the non-expert as well as applicability, particularly in industrial settings. Here, we report a simple method for the use of earth-abundant metal catalysts by general activation with sodium tert-butoxide. Using only robust air- and moisture-stable reagents and pre-catalysts, both known and, significantly, novel catalytic activities have been successfully achieved, covering hydrosilylation, hydroboration, hydrovinylation, hydrogenation and [2π+2π] alkene cycloaddition. This activation method allows for the easy use of earth-abundant metals, including iron, cobalt, nickel and manganese, and represents a generic platform for the discovery and application of non-precious metal catalysis. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Peng J.,University of Edinburgh | Docherty J.H.,University of Edinburgh | Dominey A.P.,Medicines Research Center | Thomas S.P.,University of Edinburgh
Chemical Communications | Year: 2017

A bipyridiyl-oxazoline cobalt catalyst t BuBPOCoCl2 has been developed for the Markovnikov selective hydroboration of alkenes using pinacolborane and NaOtBu as the in situ activator with up to >98 : 2 branched : linear selectivity (24 examples, 45-92% isolated yield). © 2017 American Physical Society.

Gleeson M.P.,Kasetsart University | Montanari D.,Medicines Research Center | Montanari D.,Lundbeck
Expert Opinion on Drug Metabolism and Toxicology | Year: 2012

Introduction: The most desirable chemical starting point in drug discovery is a hit or lead with a good overall profile, and where there may be issues; a clear SAR strategy should be identifiable to minimize the issue. Filtering based on drug-likeness concepts are a first step, but more accurate theoretical methods are needed to i) estimate the biological profile of molecule in question and ii) based on the underlying structureactivity relationships used by the model, estimate whether it is likely that the molecule in question can be altered to remove these liabilities. Areas covered: In this paper, the authors discuss the generation of ADMET models and their practical use in decision making. They discuss the issues surrounding data collation, experimental errors, the model assessment and validation steps, as well as the different types of descriptors and statistical models that can be used. This is followed by a discussion on how the model accuracy will dictate when and where it can be used in the drug discovery process. The authors also discuss how models can be developed to more effectively enable multiple parameter optimization. Expert opinion: Models can be applied in lead generation and lead optimization steps to i) rank order a collection of hits, ii) prioritize the experimental assays needed for different hit series, iii) assess the likelihood of resolving a problem that might be present in a particular series in lead optimization and iv) screen a virtual library based on a hit or lead series to assess the impact of diverse structural changes on the predicted properties. © 2012 Informa UK, Ltd.

Taddese B.,University of Essex | Simpson L.M.,University of Essex | Wall I.D.,Medicines Research Center | Blaney F.E.,Memprot Consulting | Reynolds C.A.,University of Essex
Methods in Enzymology | Year: 2013

The most significant advance in modeling GPCR active states has been the β2-adrenergic receptor-Gs complex as this essentially transforms active-state modeling into homology modeling. Various different molecular dynamics-based approaches for modeling active states are presented, and a number of key applications discussed. These simulations have given insights into the activation pathway, conformational changes, dimerization, hydration, the ionic lock, ligand binding, protonation, and sodium binding. Crystallography and simulations have shown that the presence of agonist alone is unlikely to be sufficient to form the active state and that restraints applied to the G protein-binding region are required. The role of various microswitches in activation is discussed, including the controversial rotamer toggle switch. The importance of explicitly simulating experimental molecular probes to understand activation is highlighted, along with the need to ensure that such molecules are well parameterized. Approaches to loop modeling are discussed. We argue that the role of successful virtual screening against active models should not be overestimated as the main conformational changes on activation occur in the intracellular region. © 2013 Elsevier Inc.

Hill A.P.,Medicines Research Center | Redman A.M.,Moore Research | Sneddon H.F.,Medicines Research Center
Green Chemistry | Year: 2015

Further to the introduction of solvent and reagent guides at GSK, the reagent guide methodology has been adapted to score common acids and bases for use in situations where the chemistry is tolerant of a number of options. The pKa of each acid and base, and information as to whether they are generally recognised as safe are included to enhance the utility of such guides. © 2015 The Royal Society of Chemistry.

Bates S.,Medicines Research Center
Drug Discovery Today | Year: 2010

Personalized medicine is the tailoring of therapies to defined subsets of patients based on their likelihood to respond to therapy or their risk of adverse events. The advent of improved genomic tools has greatly hastened our understanding of the molecular pathology of diseases, enabling us to redefine disease at the molecular level. The development of molecularly targeted therapies, coupled with improved diagnostic criteria, holds the promise of delivering a new paradigm in drug development. But how far have we come, and how close is personalized medicine to delivering on its promise? © 2009 Elsevier Ltd. All rights reserved.

Henderson R.K.,GSK | Jimenez-Gonzalez C.,Moore Research | Constable D.J.C.,Lockheed Martin | Alston S.R.,Moore Research | And 5 more authors.
Green Chemistry | Year: 2011

Solvents make a large contribution to the environmental impact of manufacturing processes of active pharmaceutical ingredients (API), as well as playing an important role in other chemical industries, with millions of tons used and disposed of each year. GlaxoSmithKline (GSK) has previously reported on the both the development of a GSK solvent selection guide and the incorporation of solvent life cycle inventory and assessment information. The GSK solvent selection guide has been further enhanced by: • Revising the assessments of factors that impact process safety, separating reactivity from fire and explosion rankings. • More than doubling the number of solvents in the guide, to a total of 110 from the initial 47. • Adding a customised solvent selection guide appropriate for medicinal chemistry and analytical laboratories. The new GSK solvent selection guide enables GSK scientists to objectively assess solvents and determine whether existing or new solvents brought to market as 'greener' alternatives truly represent a more sustainable choice or whether they are just addressing a single issue associated with sustainability. © The Royal Society of Chemistry.

Marshall L.J.,University of St. Andrews | Cable K.M.,Medicines Research Center | Botting N.P.,University of St. Andrews
Tetrahedron Letters | Year: 2010

The preparation of bis-protected phloroglucinol derivatives from a range of protected resorcinol substrates is presented. Functionalization was achieved via a two-step, one-pot iridium-catalyzed C-H activation/borylation/oxidation protocol. Our system gave high conversions to the arylboronic esters and good yields of the desired phenols following subsequent oxidation. A range of common protecting group categories was studied including alkyl, silyl, ether and ester. © 2010 Elsevier Ltd. All rights reserved.

Yang H.-T.,UK National Institute for Medical Research | Papoutsopoulou S.,UK National Institute for Medical Research | Belich M.,UK National Institute for Medical Research | Belich M.,Medicines Research Center | And 6 more authors.
Molecular and Cellular Biology | Year: 2012

The role of IκB kinase (IKK)-induced proteolysis of NF-κB1 p105 in innate immune signaling was investigated using macrophages from Nfkb1SSAA/SSAA mice, in which the IKK target serines on p105 are mutated to alanines. We found that the IKK/p105 signaling pathway was essential for TPL-2 kinase activation of extracellular signal-regulated kinase (ERK) mitogen-activate protein (MAP) kinase and modulated the activation of NF-κB. The Nfkb1SSAA mutation prevented the agonist-induced release of TPL-2 from its inhibitor p105, which blocked activation of ERK by lipopolysaccharide (LPS), tumor necrosis factor (TNF), CpG, tripalmitoyl-Cys-Ser-Lys (Pam3CSK), poly(I · C), flagellin, and R848. The Nfkb1SSAA mutation also prevented LPS-induced processing of p105 to p50 and reduced p50 levels, in addition to decreasing the nuclear translocation of RelA and cRel. Reduced p50 in Nfkb1SSAA/SSAA macrophages significantly decreased LPS induction of the IκBξ-regulated Il6 and Csf2 genes. LPS upregulation of Il12a and Il12b mRNAs was also impaired although specific blockade of TPL-2 signaling increased expression of these genes at late time points. Activation of TPL-2/ERK signaling by IKK-induced p105 proteolysis, therefore, induced a negative feedback loop to downregulate NF-κB-dependent expression of the proinflammatory cytokine interleukin-12 (IL-12). Unexpectedly, TPL-2 promoted soluble TNF production independently of IKK-induced p105 phosphorylation and its ability to activate ERK, which has important implications for the development of anti-inflammatory drugs targeting TPL-2. © 2012, American Society for Microbiology.

Poingdestre S.-J.,University of Oxford | Goodacre J.D.,Medicines Research Center | Weller A.S.,University of Oxford | Willis M.C.,University of Oxford
Chemical Communications | Year: 2012

The use of the electron-rich diphosphine ligand, dcpe, allows the efficient and highly linear selective hydroacylative coupling of aldehydes, including aryl examples, with a range of alkynes. © 2012 The Royal Society of Chemistry.

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