Publications by authors named "David R Witty"

14 Publications

  • Page 1 of 1

Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia.

ACS Med Chem Lett 2020 Sep 16;11(9):1678-1687. Epub 2020 Jul 16.

Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States.

Drugs that block voltage-gated sodium channels (Nas) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved Na blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488392PMC
September 2020

Preface.

Prog Med Chem 2020 ;59:ix-x

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http://dx.doi.org/10.1016/S0079-6468(20)30010-2DOI Listing
January 2020

Preface.

Prog Med Chem 2018;57(1):ix-x

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http://dx.doi.org/10.1016/S0079-6468(18)30010-9DOI Listing
December 2018

Crystal structures of ASK1-inhibtor complexes provide a platform for structure-based drug design.

Protein Sci 2013 Aug 3;22(8):1071-7. Epub 2013 Jul 3.

GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.

ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.
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http://dx.doi.org/10.1002/pro.2298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832043PMC
August 2013

Glucokinase. Preface.

Prog Med Chem 2013 ;52:v-vii

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http://dx.doi.org/10.1016/B978-0-444-62652-3.10000-6DOI Listing
June 2013

The large scale restructuring of pharmaceutical company research function. Preface.

Prog Med Chem 2012 ;51:v-vi

Garden Fields, Stevenage Road, St Ippolyts, Herts SG4 7PE, United Kingdom.

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http://dx.doi.org/10.1016/B978-0-12-396493-9.00005-4DOI Listing
August 2012

Drug discovery projects. Preface.

Prog Med Chem 2011 ;50:v-vi

Garden Fields, Herts SG4 7PE, United Kingdom.

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http://dx.doi.org/10.1016/b978-0-12-381290-2.00012-4DOI Listing
October 2011

Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists.

Bioorg Med Chem Lett 2008 Oct 7;18(20):5698-700. Epub 2008 Aug 7.

Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
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http://dx.doi.org/10.1016/j.bmcl.2008.08.010DOI Listing
October 2008

Biphenyl amides and isosteres as MCH R1 antagonists.

Curr Top Med Chem 2007 ;7(15):1455-70

Metabolic and Viral Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27707, USA.

The pursuit of MCH R1 antagonists for the treatment of obesity has become an active area of research for many pharmaceutical companies. The evidence supporting the use of MCH R1 antagonists for the treatment of obesity is ample, and the recent demonstration of MCH R1 antagonists' efficacy in animal models of obesity has served to augment earlier studies involving MCH peptide and transgenic animals. We report herein our search for MCH R1 antagonists from the discovery of a biphenyl amide by high throughput screening, through the optimization of the biphenyl amide to a series of constrained aryl-substituted thienopyrimidinones, and extending the application of the thienopyrimidinone substructure to other series of MCH R1 antagonists. Importantly, these MCH R1 antagonists have demonstrated efficacy in animal models of obesity through once-daily oral administration at low doses.
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http://dx.doi.org/10.2174/156802607782194743DOI Listing
November 2007

Discovery of potent and stable conformationally constrained analogues of the MCH R1 antagonist SB-568849.

Bioorg Med Chem Lett 2006 Sep 12;16(18):4872-8. Epub 2006 Jul 12.

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
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http://dx.doi.org/10.1016/j.bmcl.2006.06.061DOI Listing
September 2006

SAR of biphenyl carboxamide ligands of the human melanin-concentrating hormone receptor 1 (MCH R1): discovery of antagonist SB-568849.

Bioorg Med Chem Lett 2006 Sep 12;16(18):4865-71. Epub 2006 Jul 12.

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
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http://dx.doi.org/10.1016/j.bmcl.2006.06.056DOI Listing
September 2006

Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists.

Bioorg Med Chem Lett 2005 Nov;15(21):4867-71

Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.
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http://dx.doi.org/10.1016/j.bmcl.2005.06.107DOI Listing
November 2005

Definition of the heterocyclic pharmacophore of bacterial methionyl tRNA synthetase inhibitors: potent antibacterially active non-quinolone analogues.

Bioorg Med Chem Lett 2004 Aug;14(15):3937-41

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
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http://dx.doi.org/10.1016/j.bmcl.2004.05.070DOI Listing
August 2004

The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase.

Bioorg Med Chem Lett 2002 Nov;12(21):3171-4

GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.
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http://dx.doi.org/10.1016/s0960-894x(02)00604-2DOI Listing
November 2002