Roger John Butlin
AstraZeneca
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Publication
Featured researches published by Roger John Butlin.
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.
Bioorganic & Medicinal Chemistry Letters | 2011
Tim Luker; Lilian Alcaraz; Kamaldeep K. Chohan; Niklas Blomberg; Dearg S. Brown; Roger John Butlin; Thomas Elebring; Andrew Griffin; Simon D. Guile; Stephen St-Gallay; Britt-Marie Swahn; Steve Swallow; Michael J. Waring; Mark C. Wenlock; Paul D. Leeson
A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
Angewandte Chemie | 2012
James D. Kirkham; Roger John Butlin; Joseph P. A. Harrity
Simple as ABC: Alkynyl borane cycloadditions can be substrate-directed to assemble aromatic difluoroboranes within an extremely mild and efficient reaction manifold compared to that of traditional methods (see scheme). The aromatic boranes are readily transformed into a range of useful products.
Bioorganic & Medicinal Chemistry Letters | 2012
William Mccoull; Matthew S. Addie; Alan Martin Birch; Susan Birtles; Linda K. Buckett; Roger John Butlin; Suzanne S. Bowker; Scott Boyd; Stephen Chapman; Robert D. M. Davies; Craig S. Donald; Clive Green; Chloe Jenner; Paul D. Kemmitt; Andrew G. Leach; Graeme C. Moody; Pablo Morentin Gutierrez; Nicholas John Newcombe; Thorsten Nowak; Martin J. Packer; Alleyn T. Plowright; John Revill; Paul Schofield; Chris Sheldon; Steve Stokes; Andrew V. Turnbull; Steven Wang; David Paul Whalley; J. Matthew Wood
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Journal of Medicinal Chemistry | 2012
Jonas G. Barlind; Udo Bauer; Alan Martin Birch; Susan Birtles; Linda K. Buckett; Roger John Butlin; Robert D. M. Davies; Jan W. Eriksson; Clare D. Hammond; Ragnar Hovland; Petra Johannesson; Magnus J. Johansson; Paul D. Kemmitt; Bo T. Lindmark; Pablo Morentin Gutierrez; Tobias Noeske; Andreas Nordin; Charles O’Donnell; Annika U. Petersson; Alma Redzic; Andrew V. Turnbull; Johanna Vinblad
A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.
Bioorganic & Medicinal Chemistry Letters | 2011
Katy J. Brocklehurst; Anders Broo; Roger John Butlin; Hayley S. Brown; David S. Clarke; Öjvind Davidsson; Kristin Goldberg; Sam D. Groombridge; Elizabeth E. Kelly; Andrew G. Leach; Darren Mckerrecher; Charles O’Donnell; Simon M. Poucher; Paul Schofield; James S. Scott; Joanne Teague; Leanne Westgate; Matt J.M. Wood
GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.
Chemical Communications | 2011
Nicole C. Mancey; Nicolas Sandon; Anne-Laure Auvinet; Roger John Butlin; Werngard Czechtizky; Joseph P. A. Harrity
The enantiospecific and diastereocontrolled total synthesis of alkaloid (-)-217A is described that employs a stepwise [3+3] annelation strategy and a piperidine 2,3-cyclopropanation-ring opening reaction as the key steps.
Journal of Medicinal Chemistry | 2017
William Mccoull; Andrew Bailey; Peter Barton; Alan Martin Birch; Alastair J. H. Brown; Hayley S. Butler; Scott Boyd; Roger John Butlin; Ben Chappell; Paul Clarkson; Shelley Collins; Robert M. D. Davies; Anne Ertan; Clare D. Hammond; Jane L. Holmes; Carol Lenaghan; Anita Midha; Pablo Morentin-Gutierrez; Jane E. Moore; Piotr Raubo; Graeme R. Robb
GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.
MedChemComm | 2013
Alleyn T. Plowright; Peter Barton; Stuart Norman Lile Bennett; Alan Martin Birch; Susan Birtles; Linda K. Buckett; Roger John Butlin; Robert D. M. Davies; Anne Ertan; Pablo Morentin Gutierrez; Paul D. Kemmitt; Andrew G. Leach; Per H. Svensson; Andrew V. Turnbull; Michael J. Waring
A novel series of potent diacylglycerol acyl transferase 1 inhibitors was developed from the clinical candidate AZD3988. Replacement of the phenyl cyclohexyl-ethanoate side chain with substituted oxy-linked side chains to introduce changes in shape and polarity, reduce lipophilicity and mask the hydrogen bond donors with internal hydrogen bond acceptors led to improvements in solubility, unbound clearance and excellent selectivity over the related enzyme acyl-coenzyme A:cholesterol acyltransferase 1. A comparison of the small molecule crystal structures of compound 4 and compound 28 is described. Compounds in this series have good ADMET properties and provide an exposure-dependent decrease in circulating plasma triglyceride levels in a rat oral lipid tolerance test.
MedChemComm | 2013
Michael J. Waring; Alan Martin Birch; Susan Birtles; Linda K. Buckett; Roger John Butlin; Leonie Campbell; Pablo Morentin Gutierrez; Paul D. Kemmitt; Andrew G. Leach; Philip A. MacFaul; Charles John O'donnell; Andrew V. Turnbull
Inhibition of diacylglycerol acetyl transferase 1 is of great interest in the treatment of diabetes, obesity and other diseases that constitute the metabolic syndrome. Small molecule inhibitors of the enzyme are often dogged with physicochemical property-related problems such as poor solubility. Herein, the optimisation of a series of biphenyl acetic acid inhibitors is reported. Focus on ligand efficiency and ligand lipophilicity efficiency and a strategy based on conformational restriction led to compounds with excellent potency and ADMET properties, culminating in the discovery of AZD2353.