Publications by authors named "Angela Worby"

23 Publications

  • Page 1 of 1

Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists.

Bioorg Med Chem Lett 2013 Dec 5;23(24):6890-6. Epub 2013 Oct 5.

GlaxoSmithKline R&D, Neurology Centre of Excellence for Drug Discovery, Harlow, Essex CM19 5AW, United Kingdom. Electronic address:

This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
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http://dx.doi.org/10.1016/j.bmcl.2013.09.090DOI Listing
December 2013

The discovery of the benzazepine class of histamine H3 receptor antagonists.

Bioorg Med Chem Lett 2013 Dec 5;23(24):6897-901. Epub 2013 Oct 5.

GlaxoSmithKline R&D, Neurology CEDD, Harlow, Essex CM19 5AW, United Kingdom. Electronic address:

This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
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http://dx.doi.org/10.1016/j.bmcl.2013.09.089DOI Listing
December 2013

1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane: further insights into a class of triple re-uptake inhibitors.

Bioorg Med Chem 2011 Jun 22;19(11):3451-61. Epub 2011 Apr 22.

GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy.

Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.
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http://dx.doi.org/10.1016/j.bmc.2011.04.032DOI Listing
June 2011

5-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones: dual-acting 5-HT1 receptor antagonists and serotonin reuptake inhibitors. Part 3.

Bioorg Med Chem Lett 2010 Dec 27;20(23):7092-6. Epub 2010 Sep 27.

Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.
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http://dx.doi.org/10.1016/j.bmcl.2010.09.085DOI Listing
December 2010

Exploration of the amine terminus in a novel series of 1,2,4-triazolo-3-yl-azabicyclo[3.1.0]hexanes as selective dopamine D3 receptor antagonists.

J Med Chem 2010 Oct;53(19):7129-39

Neurosciences Centre of Excellence, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy.

A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken.
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http://dx.doi.org/10.1021/jm100832dDOI Listing
October 2010

Design and synthesis of novel tricyclic benzoxazines as potent 5-HT(1A/B/D) receptor antagonists leading to the discovery of 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045).

J Med Chem 2010 Aug;53(15):5827-43

Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.
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http://dx.doi.org/10.1021/jm100482nDOI Listing
August 2010

Triazolyl azabicyclo[3.1.0]hexanes: A class of potent and selective dopamine D(3) receptor antagonists.

ChemMedChem 2010 May;5(5):705-15

Neurosciences Centre of Excellence, Verona, Italy.

Herein we report a detailed description of the structure-activity relationships for a novel series of "C-linked" 1,2,4-triazolylazabicyclo[3.1.0]hexanes. These derivatives are endowed with very high in vitro affinity and selectivity for the dopamine D(3) receptor. An optimization with respect to undesired affinity toward the hERG potassium channel is also reported. Members of this compound series also show excellent in vitro and in vivo pharmacokinetic properties.
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http://dx.doi.org/10.1002/cmdc.201000026DOI Listing
May 2010

The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure.

Bioorg Med Chem Lett 2010 Mar 25;20(6):2013-6. Epub 2010 Jan 25.

GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, New Frontiers Science Park, Harlow, UK.

The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.
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http://dx.doi.org/10.1016/j.bmcl.2010.01.090DOI Listing
March 2010

1,2,4-Triazolyl azabicyclo[3.1.0]hexanes: a new series of potent and selective dopamine D(3) receptor antagonists.

J Med Chem 2010 Jan;53(1):374-91

Neurosciences Centre of Excellence, GlaxoSmithKline Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy.

The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.
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http://dx.doi.org/10.1021/jm901319pDOI Listing
January 2010

Dopamine D3 receptor antagonists: the quest for a potentially selective PET ligand. Part one: lead identification.

Bioorg Med Chem Lett 2009 Aug 14;19(16):4799-801. Epub 2009 Jun 14.

Cancer Therapeutics, Melbourne, Australia.

The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported.
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http://dx.doi.org/10.1016/j.bmcl.2009.06.043DOI Listing
August 2009

Dopamine D(3) receptor antagonists: The quest for a potentially selective PET ligand. Part two: Lead optimization.

Bioorg Med Chem Lett 2009 Aug 13;19(15):4011-3. Epub 2009 Jun 13.

GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Medicine Research Centre, Verona, Italy.

The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.
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http://dx.doi.org/10.1016/j.bmcl.2009.06.028DOI Listing
August 2009

Synthesis and pharmacological characterization of novel druglike corticotropin-releasing factor 1 antagonists.

J Med Chem 2008 Dec;51(23):7370-9

Neurosciences Centre of Excellence for Drug Discovery and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy.

To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
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http://dx.doi.org/10.1021/jm800744mDOI Listing
December 2008

Dihydropyrrole[2,3-d]pyridine derivatives as novel corticotropin-releasing factor-1 antagonists: mapping of the receptor binding pocket by in silico docking studies.

J Med Chem 2008 Nov;51(22):7273-86

Neurosciences Centre of Excellence for Drug Discovery and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135, Verona, Italy.

In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.
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http://dx.doi.org/10.1021/jm800743qDOI Listing
November 2008

New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part one: [h]-fused tricyclic systems.

Bioorg Med Chem Lett 2008 Feb 3;18(3):901-7. Epub 2008 Jan 3.

GlaxoSmithKline, Psychiatry Centre of Excellence for Drug Discovery, Via Fleming, 4, 37135 Verona, Italy.

The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
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http://dx.doi.org/10.1016/j.bmcl.2007.12.066DOI Listing
February 2008

New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part 2: [g]-fused and hetero-fused systems.

Bioorg Med Chem Lett 2008 Feb 4;18(3):908-12. Epub 2008 Jan 4.

GlaxoSmithKline, Psychiatry Centre of Excellence for Drug Discovery, Via Fleming, 4, 37135 Verona, Italy.

The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.
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http://dx.doi.org/10.1016/j.bmcl.2007.12.042DOI Listing
February 2008

1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D(3) receptor antagonists.

J Med Chem 2007 Oct 15;50(21):5076-89. Epub 2007 Sep 15.

Psychiatry Centre of Excellence, Molecular Discovery Research, and Safety Assessment, GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy.

The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
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http://dx.doi.org/10.1021/jm0705612DOI Listing
October 2007

Novel substituted tetrahydrotriazaacenaphthylene derivatives as potent CRF1 receptor antagonists.

Bioorg Med Chem Lett 2007 Sep 30;17(18):5218-21. Epub 2007 Jun 30.

Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithkline, Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy.

Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.
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http://dx.doi.org/10.1016/j.bmcl.2007.06.077DOI Listing
September 2007

GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models.

J Pharmacol Exp Ther 2007 Jun 27;321(3):1032-45. Epub 2007 Feb 27.

Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Ave., Harlow, Essex, CM19 5AW, UK.

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.
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http://dx.doi.org/10.1124/jpet.107.120311DOI Listing
June 2007

Studies towards the identification of a new generation of atypical antipsychotic agents.

Bioorg Med Chem Lett 2007 Jan 19;17(2):400-5. Epub 2006 Oct 19.

Psychiatry Centre of Excellence for Drug Discovery, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK.

A rational structure-activity relationship study around compound (1) is reported. The lead optimisation programme led to the identification of sulfonamide (25), a molecule combining dopamine D2/D3 receptor antagonism with serotonin 5-HT2A, 5-HT2C, 5-HT6 receptor antagonism for an effective treatment of schizophrenia. Compound (25) was shown to possess the required in vivo activity with no EPS liability.
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http://dx.doi.org/10.1016/j.bmcl.2006.10.036DOI Listing
January 2007

Pharmacological profile of antipsychotics at monoamine receptors: atypicality beyond 5-HT2A receptor blockade.

CNS Neurol Disord Drug Targets 2006 Aug;5(4):445-52

Psychiatry Centre for Excellence in Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

Antipsychotic drugs (APD) are widely prescribed for the treatment of schizophrenia. The APD are differentiated into typical and atypical based on the lower incidence of extra-pyramidal side-effects associated with the newer atypical APD. It was suggested that atypicality may arise from an interaction with the 5-hydroxytryptamine (5-HT)(2) receptor and specifically on the 5-HT(2):dopamine D(2) affinity ratio. It is now realised that multiple subtypes of these receptors exist and that in addition, atypical APD interact with many monoamine receptors. The aim of the present study was to characterise the interaction of APD with a variety of monoamine receptors in terms of both affinity and efficacy. The data produced has highlighted that the atypical profile of APD such as olanzapine and clozapine may reflect antagonism of the 5-HT(2A) and 5-HT(2C) receptors, whilst that of, ziprasidone and quetiapine may reflect partial agonist activity at the 5-HT(1A) receptor, and that of aripiprazole may reflect partial agonist activity at the 5-HT(1A) receptor as well as is its claimed partial agonist activity at the dopamine D(2) receptor.
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http://dx.doi.org/10.2174/187152706777950693DOI Listing
August 2006

Discovery and optimisation of potent, selective, ethanolamine inhibitors of bacterial phenylalanyl tRNA synthetase.

Bioorg Med Chem Lett 2005 May;15(9):2305-9

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

High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition.
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http://dx.doi.org/10.1016/j.bmcl.2005.03.003DOI Listing
May 2005

Nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase with potent antibacterial activity against gram-positive pathogens.

J Med Chem 2002 May;45(10):1959-62

Potent nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase have been derived from a file compound high throughput screening hit. Optimized compounds show excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics. Compound 11 demonstrated in vivo efficacy in an S. aureus rat abscess infection model.
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http://dx.doi.org/10.1021/jm025502xDOI Listing
May 2002