Julian A. Hudson
AstraZeneca
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Featured researches published by Julian A. Hudson.
Journal of Medicinal Chemistry | 2012
James S. Scott; Alan Martin Birch; Katy J. Brocklehurst; Anders Broo; Hayley S. Brown; Roger John Butlin; David S. Clarke; Öjvind Davidsson; Anne Ertan; Kristin Goldberg; Sam D. Groombridge; Julian A. Hudson; David Laber; Andrew G. Leach; Philip A. MacFaul; Darren Mckerrecher; Adrian Pickup; Paul Schofield; Per H. Svensson; Pernilla Sörme; Joanne Teague
G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.
Journal of Medicinal Chemistry | 2012
Alexander G. Dossetter; Howard Beeley; Jonathan Bowyer; Calum R. Cook; James J. Crawford; Jonathan E. Finlayson; Nicola Murdoch Heron; Christine Heyes; Adrian J. Highton; Julian A. Hudson; Anja Jestel; Peter W. Kenny; Stephan Krapp; Scott Martin; Philip A. MacFaul; Thomas M. McGuire; Pablo Morentin Gutierrez; Andrew D. Morley; Jeffrey James Morris; Ken Page; Lyn Rosenbrier Ribeiro; Helen Sawney; Stefan Steinbacher; Caroline L. Smith; Madeleine Vickers
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
Tetrahedron Letters | 2000
Jason Grant Kettle; Alan Wellington Faull; Shaun Fillery; Anthony Patrick Flynn; Marcus A. Hoyle; Julian A. Hudson
Abstract 2-Carboethoxy-3-diazo-3 H -indole is a substrate for rhodium(II)-catalysed alcohol O–H insertion reactions leading to 3-alkoxyindoles in good yield. The scope of the reaction is discussed.
Journal of Medicinal Chemistry | 2014
James S. Scott; Suzanne S. Bowker; Katy J. Brocklehurst; Hayley S. Brown; David S. Clarke; Alison Easter; Anne Ertan; Kristin Goldberg; Julian A. Hudson; Stefan Kavanagh; David Laber; Andrew G. Leach; Philip A. MacFaul; Darren Mckerrecher; Paul Schofield; Per H. Svensson; Joanne Teague
Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate 1 through mice toxicity studies, we observed tonic-clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone 16. This compound did not cause tonic-clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119.
MedChemComm | 2013
James S. Scott; Alan Martin Birch; Katy J. Brocklehurst; Hayley S. Brown; Kristin Goldberg; Sam D. Groombridge; Julian A. Hudson; Andrew G. Leach; Philip A. MacFaul; Darren Mckerrecher; Ruth Poultney; Paul Schofield; Per H. Svensson
Improving aqueous solubility is a challenge frequently faced within drug discovery programs. Herein we describe increases in solubility in two sub-series of GPR119 agonists through reduction of lipophilicity together with hydrogen bond acceptor modulation. Small molecule X-ray crystallography was utilised to investigate effects on solid state interactions.
Journal of Medicinal Chemistry | 2012
James J. Crawford; Peter W. Kenny; Jonathan Bowyer; Calum R. Cook; Jonathan E. Finlayson; Christine Heyes; Adrian J. Highton; Julian A. Hudson; Anja Jestel; Stephan Krapp; Scott Martin; Philip A. MacFaul; Benjamin P. McDermott; Thomas M. McGuire; Andrew D. Morley; Jeffrey James Morris; Ken Page; Lyn Rosenbrier Ribeiro; Helen Sawney; Stefan Steinbacher; Caroline L. Smith; Alexander G. Dossetter
Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH₃O)₂Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif. Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).
Bioorganic & Medicinal Chemistry Letters | 2012
John G. Cumming; Justin Fairfield Bower; David Waterson; Alan Wellington Faull; Philip Jeffrey Poyser; Paul Turner; Benjamin P. McDermott; Andrew Campbell; Julian A. Hudson; Michael James; Jon Winter; Christine Wood
A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl]piperazine-1-carboxamide, are described.
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.
Journal of Medicinal Chemistry | 2017
James S. Scott; Sébastien L. Degorce; Rana Anjum; Janet D. Culshaw; Robert D. M. Davies; Nichola L. Davies; Keith Dillman; James E. Dowling; Lisa Drew; Andrew D. Ferguson; Sam D. Groombridge; Christopher Thomas Halsall; Julian A. Hudson; Scott Lamont; Nicola Lindsay; Stacey K. Marden; Michele Mayo; J. Elizabeth Pease; David Perkins; Jennifer H. Pink; Graeme R. Robb; Alan Rosen; Minhui Shen; Claire McWhirter; Dedong Wu
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
Bioorganic & Medicinal Chemistry Letters | 2012
Alexander G. Dossetter; Jonathan Bowyer; Calum R. Cook; James J. Crawford; Jonathan E. Finlayson; Nicola Murdoch Heron; Christine Heyes; Adrian J. Highton; Julian A. Hudson; Anja Jestel; Stephan Krapp; Philip A. MacFaul; Thomas M. McGuire; Andrew D. Morley; Jeffrey James Morris; Ken Page; Lyn Rosenbrier Ribeiro; Helen Sawney; Stefan Steinbacher; Caroline Smith
The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.