Iain Simpson
AstraZeneca
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Publication
Featured researches published by Iain Simpson.
Organic Letters | 2013
Nicola Caldwell; Craig Jamieson; Iain Simpson; Tell Tuttle
A base-mediated procedure for the amidation of unactivated esters with amino alcohols is reported. Optimization and exemplification of the catalytic process are described, furnishing products in 40-100% isolated yield.
Bioorganic & Medicinal Chemistry Letters | 2009
Alan Martin Birch; Peter W. Kenny; Iain Simpson; Paul R.O. Whittamore
Matched molecular pair analysis has been used in design of inhibitors of glycogen phosphorylase.
Bioorganic & Medicinal Chemistry Letters | 2011
Richard Ducray; Iain Simpson; Frederic Henri Jung; J. Willem M. Nissink; Peter W. Kenny; Martina Fitzek; Graeme Walker; Lara Ward; Kevin Hudson
We disclose a novel series of insulin-like growth factor-1 receptor kinase inhibitors based on the 3-(pyrimidin-4-yl)-imidazo[1,2-a]pyridine scaffold. The influence on the inhibitory activity of substitution on the imidazopyridine and at the C5 position of the pyrimidine is discussed. In the course of this optimization, we discovered a potent and selective inhibitor with suitable pharmacokinetics for oral administration.
Organic Letters | 2013
Thomas James; Iain Simpson; J. Andrew Grant; Visuvanathar Sridharan; Adam Nelson
Ring-opening of cyclic sulfamidates with propargylic sulfonamides yielded substrates for a gold-catalyzed cyclization to yield tetrahydropyrazines. Manipulation of the tetrahydropyrazines, by reduction or using multicomponent reactions, yielded piperazine scaffolds in which substitution of the carbon atoms was varied. Such scaffolds may have value in the synthesis of novel screening compounds with lead-like molecular properties.
Bioorganic & Medicinal Chemistry Letters | 2011
Richard Ducray; Clifford David Jones; Frederic Henri Jung; Iain Simpson; Jon Owen Curwen; Martin Pass
Following the discovery of imidazopyridine 1 as a potent IGF-1R tyrosine kinase inhibitor, the aniline part has been modified with the aim to optimize the properties of this series. The structure-activity relationships against IGF-1R kinase activity as well as inhibition of the hERG ion channel are discussed.
Journal of Organic Chemistry | 2014
Nicola Caldwell; Peter S. Campbell; Craig Jamieson; Frances Potjewyd; Iain Simpson; Allan J. B. Watson
A catalytic protocol for the base-mediated amidation of unactivated esters with amino alcohol derivatives is reported. Investigations into mechanistic aspects of the process indicate that the reaction involves an initial transesterification, followed by an intramolecular rearrangement. The reaction is highly general in nature and can be extended to include the synthesis of oxazolidinone systems through use of dimethyl carbonate.
Organic Letters | 2014
Matthew R. Tatton; Iain Simpson; Timothy J. Donohoe
The olefin cross-metathesis reaction allows rapid access to 1,5-dicarbonyl intermediates which, upon treatment with a primary or secondary amine, allow the synthesis of a range of multisubstituted carbocyclic aryl amines. This de novo arene synthesis yields nonclassical substitution patterns in a regioselective and predictable approach that is compatible with several functional groups.
Journal of Medicinal Chemistry | 2016
Stuart Jones; Jonathan Ahmet; Kelly Ayton; Matthew Ball; Mark Cockerill; Emma Fairweather; Nicola S. Hamilton; Paul B. Harper; James R. Hitchin; Allan M. Jordan; Colin Levy; Ruth Lopez; Edward A. McKenzie; Martin J. Packer; Darren Plant; Iain Simpson; Peter Simpson; Ian W. Sinclair; Tim Somervaille; Helen Small; Gary J. Spencer; Graeme Thomson; Michael Tonge; Ian Waddell; Jarrod Walsh; Bohdan Waszkowycz; Mark Wigglesworth; Daniel H. Wiseman; Donald J. Ogilvie
A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.
Organic Letters | 2014
Allan Dishington; J. Lyman Feron; Kathryn Gill; Mark A. Graham; Ian A. Hollingsworth; Jennifer H. Pink; Andrew Roberts; Iain Simpson; Matthew Tatton
4-Alkyl- and 4-H-pyrazoles were sequentially metalated using TMPMgCl·LiCl, and their reaction with electrophiles afforded 3-aryl-4-alkyl-5-cyanopyrazoles.
Journal of Medicinal Chemistry | 2017
Paul A. Bethel; Calum R. Cook; Emma Davies; J.E. Debreczeni; Gary Fairley; Lyman Feron; Vikki Flemington; Mark A. Graham; Ryan Greenwood; Nicola Griffin; Lyndsey Hanson; Philip Hopcroft; Tina Howard; Julian A. Hudson; Michael R. James; Clifford David Jones; Christopher R. Jones; Scott Lamont; Richard J. Lewis; Nicola Lindsay; Karen Roberts; Iain Simpson; Steve St-Gallay; Steve Swallow; Jia Tang; Michael Tonge; Zhenhua Wang; Baochang Zhai
There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.