19 results on '"James Michael Woolven"'
Search Results
2. Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors
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Emmanuel Hubert Demont, Jonathan Thomas Seal, Stephen John Atkinson, Anna K. Bassil, Paola Grandi, Robert J. Watson, Thomas George Christopher Hayhow, James Gray, Chun-wa Chung, Aylott Helen Elizabeth, Alexander N Phillipou, Darren Jason Mitchell, James Michael Woolven, Inmaculada Rioja, Laurie J. Gordon, Francesco Rianjongdee, Paul Bamborough, Ian D. Wall, Rab K. Prinjha, Alex Preston, Lee Andrew Harrison, and Cassie Messenger
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0303 health sciences ,Drug discovery ,Cell Cycle Proteins ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Bromodomain ,Small Molecule Libraries ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Protein Domains ,chemistry ,Drug Design ,Amide ,Drug Discovery ,Humans ,Molecular Medicine ,Acetamide ,Transcription Factors ,030304 developmental biology - Abstract
A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).
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- 2021
3. The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor
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Stephen John Atkinson, Royston C. B. Copley, Matthew J Lindon, Rab K. Prinjha, Alex Preston, James Michael Woolven, Jonathan Thomas Seal, Chun-wa Chung, James Gray, Thomas George Christopher Hayhow, Laurie J. Gordon, Emmanuel Hubert Demont, Aylott Helen Elizabeth, Paola Grandi, Lee Andrew Harrison, Inmaculada Rioja, Robert J. Watson, Simon Taylor, Cassie Messenger, Ian D. Wall, Anne-Marie Michon, Darren Jason Mitchell, and Paul Bamborough
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Male ,Stereochemistry ,Protein domain ,Anti-Inflammatory Agents ,Administration, Oral ,Cell Cycle Proteins ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Ligands ,Structure-Activity Relationship ,Dogs ,Protein Domains ,In vivo ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Rats, Wistar ,Binding site ,Binding Sites ,Chemistry ,Ligand ,Hydrogen Bonding ,Amides ,Phenotype ,Rats ,Bromodomain ,Molecular Medicine ,Selectivity ,Half-Life ,Transcription Factors - Abstract
The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (15, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, 20 (GSK620) and 56 (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.
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- 2020
4. Design and Synthesis of a Highly Selective and In Vivo-Capable Inhibitor of the Second Bromodomain of the Bromodomain and Extra Terminal Domain Family of Proteins
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Peter D. Craggs, Darren Jason Mitchell, Rab K. Prinjha, Alex Preston, James Michael Woolven, Laurie J. Gordon, Simon Taylor, Paul Bamborough, Chun-wa Chung, Paola Grandi, James Gray, Francesco Rianjongdee, Matthew J Lindon, Anne-Marie Michon, Emma J. Jones, Inmaculada Rioja, Robert J. Watson, Ian D. Wall, Stephen John Atkinson, Emmanuel Hubert Demont, and Jonathan Thomas Seal
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0303 health sciences ,Chemistry ,Protein domain ,Highly selective ,01 natural sciences ,Phenotype ,In vitro ,0104 chemical sciences ,Cell biology ,Bromodomain ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,In vivo ,Drug Discovery ,Molecular Medicine ,Structure–activity relationship ,Binding site ,030304 developmental biology - Abstract
Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of in vitro phenotypic assays and in vivo pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical in vitro and in vivo characterization.
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- 2020
5. GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family
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Anne-Marie Michon, Rab K. Prinjha, Alex Preston, Laurie J. Gordon, Inmaculada Rioja, Pierre Thesmar, Emmanuel Hubert Demont, James Michael Woolven, Stephen John Atkinson, Jon T. Seal, Cassie Messenger, Lee Andrew Harrison, Paola Grandi, Darren Jason Mitchell, Robert J. Watson, Simon Taylor, Chun-wa Chung, James Gray, Antonia J. Lewis, Ian D. Wall, Dave Lugo, and Paul Bamborough
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010405 organic chemistry ,business.industry ,Organic Chemistry ,chemical and pharmacologic phenomena ,hemic and immune systems ,Pharmacology ,Highly selective ,01 natural sciences ,Biochemistry ,In vitro ,0104 chemical sciences ,Bromodomain ,010404 medicinal & biomolecular chemistry ,Safety profile ,In vivo ,Drug Discovery ,Medicine ,business - Abstract
[Image: see text] Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.
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- 2020
6. Optimization of a series of 2,3-dihydrobenzofurans as highly potent, second bromodomain (BD2)-selective, bromo and extra-terminal domain (BET) inhibitors
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Ian D. Wall, Thomas Grimes, Laurie J. Gordon, James Michael Woolven, Simon Taylor, Robert P. Davis, Simon C. C. Lucas, Chun-wa Chung, James J R Gray, Paola Grandi, Nicholas C. O. Tomkinson, Rab K. Prinjha, Robert J. Watson, Inmaculada Rioja, Alex Preston, Alexander N Phillipou, Stephen John Atkinson, and Emmanuel Hubert Demont
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RM ,QL ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Proteins ,Combinatorial chemistry ,In vitro ,Bromodomain ,RS ,Structure-Activity Relationship ,Solubility ,Pharmacokinetics ,In vivo ,Drug Discovery ,Humans ,Molecular Medicine ,Selectivity ,Benzofurans - Abstract
Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.
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- 2021
7. Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors
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Alex Phillipou, Ryan G. Kruger, Simon Taylor, Chun-wa Chung, Rab K. Prinjha, Laurie J. Gordon, Robert J. Watson, James Gray, Alex Preston, James J. Foley, Cassie Messenger, Anna K. Bassil, Inmaculada Rioja, James Michael Woolven, Xi-Ping Zhang, Francesco Rianjongdee, Paola Grandi, Jeanne J. Matteo, Anastasia Wyce, Ian D. Wall, Paul Bamborough, Darren Jason Mitchell, Lee Andrew Harrison, Michael T. McCabe, Stephen John Atkinson, Jonathan Thomas Seal, and Emmanuel Hubert Demont
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Improved solubility ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Stereochemistry ,Proteins ,Pyrazole ,Scaffold hopping ,Bromodomain ,chemistry.chemical_compound ,Safety profile ,Structure-Activity Relationship ,Drug Discovery ,Molecular Medicine ,Humans ,Pyrazoles ,Furans ,Pyrrole - Abstract
The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.
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- 2021
8. Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase
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Stéphane Sautet, Emilie Jigorel, Nicolas Faucher, Jamel Meslamani, Lara Kathryn Leister, Pascal Grondin, Julie A. Cox, Bryan W. King, Pamela Nassau, Gemma Victoria White, Brad J. Geddes, Alain Claude-Marie Daugan, Helen H. Sun, Michael T. Ouellette, Pauline Lamoureux, Elizabeth J. Rivera, Scott B. Berger, James H. Thorpe, Philip A. Harris, J. Mosley, Susan E. Hutchinson, Frédéric Donche, John Bertin, Sandra J. Hoffman, Natalie Wellaway, Patrick M. Eidam, Paris Ward, Florent Potvain, Clark A. Sehon, Sebastien Andre Campos, Robert W. Marquis, Peter J. Gough, Mukesh K. Mahajan, Veronique Beneton, Jae U. Jeong, Michelle C. Schaeffer, John D. Lich, Allison M. Beal, Rakesh Nagilla, James Michael Woolven, Bonnie L. Hoffman, Anderson Niall Andrew, Marie-Hélène Fouchet, Deepak Bandyopadhyay, Carol A. Capriotti, Rachel D. Totoritis, Joshua N. Finger, Kishore K. Pasikanti, David D. Wisnoski, Sze-Ling Ng, Nino Campobasso, Nicolas George, and Michael Reilly
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Models, Molecular ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,Necroptosis ,Biological Availability ,Inflammation ,Pharmacology ,01 natural sciences ,Cell Line ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,In vivo ,Psoriasis ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Enzyme Inhibitors ,030304 developmental biology ,0303 health sciences ,Kinase ,Chemistry ,RNA-Binding Proteins ,Haplorhini ,medicine.disease ,Ulcerative colitis ,High-Throughput Screening Assays ,Rats ,0104 chemical sciences ,Mice, Inbred C57BL ,Nuclear Pore Complex Proteins ,010404 medicinal & biomolecular chemistry ,Drug Design ,Rheumatoid arthritis ,Chronic Disease ,Pyrazoles ,Molecular Medicine ,medicine.symptom ,Retinitis Pigmentosa - Abstract
RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.
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- 2019
9. A Perspective on Water Site Prediction Methods for Structure Based Drug Design
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Xuan Hong, James Michael Woolven, Kaushik Raha, Colin M. Edge, Ian D. Wall, Eric S. Manas, Alan P. Graves, Guanglei Cui, and Armelle Le Gall
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Structure (mathematical logic) ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Interface (Java) ,Perspective (graphical) ,Proteins ,Water ,Nanotechnology ,General Medicine ,010402 general chemistry ,Ligands ,01 natural sciences ,Data science ,Field (computer science) ,0104 chemical sciences ,law.invention ,law ,Prediction methods ,Drug Design ,Drug Discovery ,CLARITY ,Structure based ,Thermodynamics - Abstract
Over the last decade, a number of computational methods have been developed, which attempt to evaluate the thermodynamic properties of individual water molecules at the solute-solvent interface, in order to assess contributions to protein-ligand binding. In some cases, these tools tell us what we already know, e.g. that hydrophobic pockets prefer lipophilic substituents, and in other cases the methods only seem to add clarity when retrospectively applied. Hence we have grappled with how to utilize such approaches to understand non-intuitive results and to generate chemistry ideas that otherwise would not have been developed. Here we provide our perspective on these methods and describe how results have been interpreted and applied. We include examples from GSK and elsewhere that highlight how water methods have been (1) utilized retrospectively to explain non-intuitive structure- activity relationships and (2) applied prospectively for chemistry design. Finally, we discuss where this field of study could lead to maximal impact in drug discovery research.
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- 2016
10. Fragment-Based Discovery of Bromodomain Inhibitors Part 1: Inhibitor Binding Modes and Implications for Lead Discovery
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Chun-wa Chung, Paul Bamborough, Anthony W. Dean, and James Michael Woolven
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Models, Molecular ,Pyridines ,Molecular Sequence Data ,Quantitative Structure-Activity Relationship ,Cell Cycle Proteins ,Fluorescence Polarization ,Computational biology ,Protein Serine-Threonine Kinases ,Crystallography, X-Ray ,Fragment (logic) ,Signaling proteins ,Drug Discovery ,Humans ,Histone code ,Amino Acid Sequence ,Epigenetics ,Acetaminophen ,Quinazolinones ,Genetics ,Molecular Structure ,Chemistry ,Indolizines ,Nuclear Proteins ,RNA-Binding Proteins ,Small molecule ,Pyrrolidinones ,Protein Structure, Tertiary ,Bromodomain ,Molecular Medicine ,Peptidomimetics ,Protein Binding ,Transcription Factors - Abstract
Bromodomain-containing proteins are key epigenetic regulators of gene transcription and readers of the histone code. However, the therapeutic benefits of modulating this target class are largely unexplored due to the lack of suitable chemical probes. This article describes the generation of lead molecules for the BET bromodomains through screening a fragment set chosen using structural insights and computational approaches. Analysis of 40 BRD2/fragment X-ray complexes highlights both shared and disparate interaction features that may be exploited for affinity and selectivity. Six representative crystal structures are then exemplified in detail. Two of the fragments are completely new bromodomain chemotypes, and three have never before been crystallized in a bromodomain, so our results significantly extend the limited public knowledge-base of crystallographic small molecule/bromodomain interactions. Certain fragments (including paracetamol) bind in a consistent mode to different bromodomains such as CREBBP, suggesting their potential to act as generic bromodomain templates. An important implication is that the bromodomains are not only a phylogenetic family but also a system in which chemical and structural knowledge of one bromodomain gives insights transferrable to others.
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- 2012
11. Heteroalicyclic carboxamidines as inhibitors of inducible nitric oxide synthase; the identification of (2R)-2-pyrrolidinecarboxamidine as a potent and selective haem-co-ordinating inhibitor
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James Michael Woolven, Simon Teanby Hodgson, Miriam Crowe, Linda J. Russell, Wendy Karen Alderton, John Dawson, C. Lynn Chambers, Christopher Charles Frederick Hamlett, Richard G. Knowles, Richard Stocker, Robert J. Young, Paul John Beswick, David W. Brown, Anthony D R Angell, and Savvas Kleanthous
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Models, Molecular ,Proline ,Stereochemistry ,Clinical Biochemistry ,Amidines ,Nitric Oxide Synthase Type II ,Pharmaceutical Science ,Heme ,Biochemistry ,Chemical synthesis ,Nitric oxide ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Heterocyclic Compounds ,Enos ,Drug Discovery ,medicine ,Humans ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,biology ,Organic Chemistry ,Glutamate receptor ,biology.organism_classification ,Enzyme Activation ,Nitric oxide synthase ,Enzyme ,Mechanism of action ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,medicine.symptom - Abstract
Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC50 = 0.12 μM) and selective iNOS inhibitor (>100-fold vs both eNOS and nNOS), with probable binding to the key anchoring glutamate residue and co-ordination to the haem iron.
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- 2011
12. Aryl aminopyrazole benzamides as oral non-steroidal selective glucocorticoid receptor agonists
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Simon J. F. Macdonald, Graham I. Somers, Natalie Rayner, Tony W. J. Cooper, Iain Mcfarlane Mclay, James Michael Woolven, Simon Taylor, Rosemary Z. Sasse, Gordon G. Weingarten, Diane Mary Coe, Heather A. Barnett, Tracy Jane Shipley, Iain Uings, Phil A. Skone, Torquil I. Jack, and Haydn Terence Jones
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medicine.medical_specialty ,Prednisolone ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Receptors, Glucocorticoid ,Internal medicine ,Drug Discovery ,Glucocorticoid Receptor Agonists ,medicine ,Animals ,Humans ,Structure–activity relationship ,Potency ,Molecular Biology ,Aryl ,Organic Chemistry ,In vitro ,Rats ,Endocrinology ,chemistry ,Benzamides ,Lipophilicity ,Pyrazoles ,Molecular Medicine ,Hydrophobic and Hydrophilic Interactions ,Glucocorticoid ,medicine.drug - Abstract
Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.g., 16e).
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- 2009
13. Discovery of 4-{4-[3-(Pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H- pyran-4-yl)benzamide (GW788388): A Potent, Selective, and Orally Active Transforming Growth Factor-β Type I Receptor Inhibitor
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James Michael Woolven, Eugene T. Grygielko, Françoise Gellibert, Neil Mathews, Stéphane Huet, Nicholas J. Laping, Angela Patikis, Cécile Bertho-Ruault, Anne-Charlotte de Gouville, and Van-Loc Nguyen
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Liver Cirrhosis ,Male ,Models, Molecular ,medicine.medical_specialty ,Receptor, Transforming Growth Factor-beta Type I ,Administration, Oral ,Protein Serine-Threonine Kinases ,Puromycin Aminonucleoside ,Pyrazole ,Pharmacology ,Kidney ,Collagen Type I ,Dimethylnitrosamine ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Growth factor receptor ,Oral administration ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,RNA, Messenger ,Benzamide ,biology ,Chemistry ,Kidney metabolism ,Transforming growth factor beta ,Fibrosis ,Rats ,Collagen Type I, alpha 1 Chain ,Endocrinology ,Puromycin ,Acute Disease ,Benzamides ,biology.protein ,Pyrazoles ,Molecular Medicine ,Activin Receptors, Type I ,Receptors, Transforming Growth Factor beta - Abstract
Inhibitors of transforming growth factor beta (TGF-beta) type I receptor (ALK5) offer a novel approach for the treatment of fibrotic diseases such as renal, hepatic, and pulmonary fibrosis. The optimization of a novel phenylpyridine pyrazole series (1a) led to the identification of potent, selective, and orally active ALK5 inhibitors. The cellular potency and pharmacokinetics profiles of these derivatives were improved and several compounds presented antifibrotic activity when orally administered to rats in an acute liver model of dimethylnitrosamine- (DMN-) induced expression of collagen IA1 mRNA, a major gene contributing to excessive extra cellular matrix deposit. One of the most potent ALK5 inhibitors identified in this chemical series, compound 13d (GW788388), reduced the expression of collagen IA1 by 80% at a dose of 1 mg/kg twice a day (b.i.d.). This compound significantly reduced the expression of collagen IA1 mRNA when administered orally at 10 mg/kg once a day (u.i.d.) in a model of puromycin aminonucleoside-induced renal fibrosis.
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- 2006
14. Identification of 1,5-Naphthyridine Derivatives as a Novel Series of Potent and Selective TGF-β Type I Receptor Inhibitors
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‡ Marie-Hélène Fouchet, Valerie Boullay, Francoise Jeanne Gellibert, Anne-Charlotte De Gouville, Victoria Lucy Helen Lovegrove, Ward Smith, Stéphane Huet, C. A. Janson, Neil Mathews, Gael Krysa, ‡ Van-Loc Nguyen, Ruolan Wang, David Hartley, James Michael Woolven, Alain Laroze, Helen Susanne Goodland, and Stéphane Sautet
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Stereochemistry ,Receptor, Transforming Growth Factor-beta Type I ,Protein Serine-Threonine Kinases ,Pyrazole ,Crystallography, X-Ray ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Aminothiazole ,Drug Discovery ,TGF beta signaling pathway ,Humans ,Structure–activity relationship ,Naphthyridines ,Phosphorylation ,Binding site ,Protein kinase A ,Binding Sites ,Autophosphorylation ,Biochemistry ,chemistry ,Docking (molecular) ,Pyrazoles ,Molecular Medicine ,Activin Receptors, Type I ,Receptors, Transforming Growth Factor beta ,Protein Binding - Abstract
Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.
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- 2004
15. Design and Synthesis of Pyrrolidine-5,5‘-trans-Lactams (5-Oxo-hexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 4. Antiviral Activity and Plasma Stability
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Deborah L. Jackson, Graham J Hart, Angela Patikis, Gordon G. Weingarten, Nigel R. Parry, Alan D. Borthwick, James Michael Woolven, Terry M. Haley, Dave E. Davies, Anne M. Exall, Peter Franz Ertl, and Naimisha Trivedi
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Models, Molecular ,Human cytomegalovirus ,Lactams ,Stereochemistry ,medicine.drug_class ,medicine.medical_treatment ,Guinea Pigs ,Biological Availability ,Cytomegalovirus ,Enzyme-Linked Immunosorbent Assay ,Carboxamide ,Eye ,Antiviral Agents ,Mass Spectrometry ,Substrate Specificity ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Protease Inhibitors ,Pyrroles ,Protease inhibitor (pharmacology) ,Ganciclovir ,Cells, Cultured ,Protease ,biology ,Serine Endopeptidases ,Brain ,medicine.disease ,Kinetics ,Benzothiazole ,chemistry ,Enzyme inhibitor ,Drug Design ,biology.protein ,Lactam ,Molecular Medicine ,Indicators and Reagents ,Half-Life - Abstract
A series of chiral, (S)-proline-alpha-methylpyrrolidine-5,5-trans-lactam serine protease inhibitors has been developed as antivirals of human cytomegalovirus (HCMV). The SAR of the functionality on the proline nitrogen has shown that derivatives of para-substituted phenyl ureas > para-substituted phenyl sulfonamides > para-substituted phenyl carboxamide for activity against HCMV deltaAla protease, producing para-substituted phenyl ureas with single figure nM potency (K(i)) against the viral enzyme. The SAR of the functionality on the lactam nitrogen has defined the steric and electronic requirements for high human plasma stability while retaining good activity against HCMV protease. The combination of high potency against HCMV deltaAla protease and high human plasma stability has produced compounds with significant in vitro antiviral activity against human cytomegalovirus with the 6-hydroxymethyl benzothiazole derivative 72 being equivalent in potency to ganciclovir. The parent benzothiazole 56 had good pharmacokinetics in dogs with 29% bioavailability and good brain and ocular penetration in guinea pigs.
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- 2003
16. Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy
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Gareth Wayne, Aoife C. Maxwell, Catherine M. Alder, Amanda J. Campbell, Aurelie C. Champigny, Donald O. Somers, Sean M. Lynn, Martin Ambler, Christopher J. Tame, Angela M. Deakin, Chris J. Mooney, Tim Longstaff, Callum Scullion, Ian Edward David Smith, James Michael Woolven, Onkar M. P. Singh, John D. Harling, Carol A. Harris, and Caroline Wilson
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chemistry.chemical_compound ,Nonsteroidal ,Chemistry ,Kinase ,Organic Chemistry ,Drug Discovery ,Computational biology ,Bioinformatics ,Biochemistry - Abstract
Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinases, particularly AurA and AurB. A template-hopping strategy was used to identify a series of aminobenzothiazole Itk inhibitors, which utilized an inherently more selective hinge binding motif. Crystallography and modeling were used to rationalize the observed selectivity. Initial exploration of the SAR around this series identified potent Itk inhibitors in both enzyme and cellular assays.
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- 2013
17. Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials
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Jose M. Bueno, Clive Yeates, Jesús Chicharro, Domingo Gargallo-Viola, Jose M. Fiandor, Mary Pudney, Neil J. Cheesman, Helen Trimming, James Michael Woolven, John F. Batchelor, Hudson Alan Thomas, Federico Gómez de las Heras, Esther Fernández, Edward C. Capon, María Luisa León, Esperanza Herreros, and Mitch Fry
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Pyridones ,Plasmodium falciparum ,chemistry.chemical_compound ,Antimalarials ,Mice ,Structure-Activity Relationship ,Parasitic Sensitivity Tests ,In vivo ,Chloroquine ,parasitic diseases ,Drug Discovery ,medicine ,Animals ,IC50 ,biology ,Chemistry ,Clopidol ,Plasmodium yoelii ,biology.organism_classification ,In vitro ,Malaria ,Biochemistry ,Coenzyme Q – cytochrome c reductase ,Molecular Medicine ,medicine.drug - Abstract
A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.
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- 2008
18. A critical assessment of docking programs and scoring functions
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C. Webster Andrews, James Michael Woolven, Millard H. Lambert, Semus Simon, Gregory L. Warren, Anna-Maria Capelli, Giovanna Tedesco, Catherine E. Peishoff, Martha S. Head, Wall Ian David, Neysa Nevins, Mika Lindvall, Judith LaLonde, Stefan Senger, and Brian Clarke
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Lead Finder ,Models, Molecular ,Quantitative structure–activity relationship ,Virtual screening ,Binding Sites ,Chemistry ,Molecular Conformation ,Proteins ,Quantitative Structure-Activity Relationship ,Computational biology ,Ligand (biochemistry) ,Bioinformatics ,Ligands ,Scoring functions for docking ,Protein–ligand docking ,Docking (molecular) ,Searching the conformational space for docking ,Drug Design ,Drug Discovery ,Molecular Medicine ,Algorithms ,Software ,Protein Binding - Abstract
Docking is a computational technique that samples conformations of small molecules in protein binding sites; scoring functions are used to assess which of these conformations best complements the protein binding site. An evaluation of 10 docking programs and 37 scoring functions was conducted against eight proteins of seven protein types for three tasks: binding mode prediction, virtual screening for lead identification, and rank-ordering by affinity for lead optimization. All of the docking programs were able to generate ligand conformations similar to crystallographically determined protein/ligand complex structures for at least one of the targets. However, scoring functions were less successful at distinguishing the crystallographic conformation from the set of docked poses. Docking programs identified active compounds from a pharmaceutically relevant pool of decoy compounds; however, no single program performed well for all of the targets. For prediction of compound affinity, none of the docking programs or scoring functions made a useful prediction of ligand binding affinity.
- Published
- 2006
19. Design and synthesis of pyrrolidine-5,5-trans-lactams (5-oxohexahydropyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 2. Potency and chirality
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Anne M. Exall, Graham J Hart, Onkar M. P. Singh, Peter Franz Ertl, James Michael Woolven, Andrew J Crame, Alan D. Borthwick, Terry M. Haley, Gordon G. Weingarten, Andrew M. Mason, and Andrew M K Pennell
- Subjects
Models, Molecular ,Lactams ,Stereochemistry ,medicine.medical_treatment ,Cytomegalovirus ,Crystallography, X-Ray ,Antiviral Agents ,Pyrrolidine ,Mass Spectrometry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Thrombin ,Drug Discovery ,polycyclic compounds ,medicine ,Structure–activity relationship ,Protease Inhibitors ,Pyrroles ,chemistry.chemical_classification ,Protease ,Binding Sites ,biology ,Serine Endopeptidases ,Active site ,Stereoisomerism ,biochemical phenomena, metabolism, and nutrition ,Protease inhibitor (biology) ,Enzyme ,chemistry ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,medicine.drug - Abstract
The stereospecific synthesis of a series of alpha-methylpyrrolidine-5,5-trans-lactam inhibitors of human cytomegalovirus (HCMV) protease is described. Examination of the SAR in this series has defined the size and chirality of the alpha-substituent, optimized the acyl substituent on the lactam nitrogen, and defined the steric constraint of this functionality. The SAR of the functionality on the pyrrolidine nitrogen of the trans-lactam has been investigated, and this has led to the discovery of potent serine protease inhibitors that are highly selective for the viral enzyme over the mammalian enzymes elastase, thrombin, and acetylcholine esterase. The mechanism of action of our lead compounds has been established by mass spectrometry, and enzymatic degradation of HCMV deltaAla protease acylated with these inhibitors showed that Ser 132 is the active site nucleophile. The crystal structure of HCMV protease was obtained and used to model the conformationally restricted, chiral (S)-proline-alpha-methyl-5,5-trans-lactams into the active site groove of the enzyme, enabling us to direct and rationalize the SAR in this series. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the dansyl-(S)-proline alpha-methyl-5,5-trans-lactam template, which have low nanomolar activity against the viral enzyme.
- Published
- 2002
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