Paul W Smith

Publications (17)51 Total impact

• Article: Radiosynthesis and in vivo evaluation of [(11)C]MP-10 as a positron emission tomography radioligand for phosphodiesterase 10A.

  Christophe Plisson, Cristian Salinas, David Weinzimmer, David Labaree, Shu-Fei Lin, Yu-Shin Ding, Steen Jakobsen, Paul W Smith, Kawanishi Eiji, Richard E Carson, Roger N Gunn, Eugenii A Rabiner
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  ABSTRACT: The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [(11)C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET. A procedure was developed for labeling MP-10 with carbon-11. [(11)C]MP-10 was evaluated in vivo both in the pig and baboon brain. Alkylation of the corresponding desmethyl compound with [(11)C]methyl iodide produced [(11)C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [(11)C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1-2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [(11)C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [(11)C]MP-10 were slower, reaching peak tissue concentrations at 30-60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [(11)C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V(T)) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP(ND)) as the outcome measure of specific binding. Quantification of [(11)C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP(ND) estimates consistent with those obtained by the two-tissue compartment model. We demonstrated that [(11)C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET.
  Nuclear Medicine and Biology 08/2011; 38(6):875-84. · 3.02 Impact Factor
• Article: The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.

  Dale J Johnson, Ian T Forbes, Steve P Watson, Vincenzo Garzya, Graeme I Stevenson, Graham R Walker, Harminder S Mudhar, Sean T Flynn, Paul A Wyman, Paul W Smith, Graham S Murkitt, Adam J Lucas, Claudette R Mookherjee, Jeannette M Watson, Jane E Gartlon, Andrea M Bradford, Fiona Brown
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  ABSTRACT: A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.
  Bioorganic & medicinal chemistry letters 09/2010; 20(18):5434-8. · 2.65 Impact Factor
• Article: Discovery of N-[(2S)-5-(6-fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a novel clinical AMPA receptor positive modulator.

  Simon E Ward, Mark Harries, Laura Aldegheri, Daniele Andreotti, Stuart Ballantine, Benjamin D Bax, Andrew J Harris, Andy J Harker, Jesper Lund, Rosemary Melarange, [......], Claudette Mookherjee, Julie Mosley, Marta Neve, Beatrice Oliosi, Roberto Profeta, Kathrine J Smith, Paul W Smith, Simone Spada, Kevin M Thewlis, Shahnaz P Yusaf
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  ABSTRACT: A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
  Journal of Medicinal Chemistry 08/2010; 53(15):5801-12. · 4.80 Impact Factor
• Article: The identification a novel, selective, non-steroidal, functional glucocorticoid receptor antagonist.

  Joseph Rimland, Angela Dunne, Suchete S Hunjan, Rosemary Sasse, Iain Uings, Dino Montanari, Matilde Caivano, Poonam Shah, David Standing, David Gray, David Brown, William Cairns, Ryan Trump, Paul W Smith, Nicolas Bertheleme, Pier D'Alessandro, Sheraz Gul, Mythily Vimal, David N Smith, Stephen P Watson
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  ABSTRACT: The identification of novel, potent, non-steroidal/small molecule functional GR antagonist GSK1564023A selective over PR is described. Associated structure-activity relationships and the process of optimisation of an initial HTS hit are also described.
  Bioorganic & medicinal chemistry letters 02/2010; 20(7):2340-3. · 2.65 Impact Factor
• Article: Therapeutic utility of NK3 receptor antagonists for the treatment of schizophrenia.

  Lee A Dawson, Paul W Smith
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  ABSTRACT: The dopaminergic and glutamatergic hypotheses dominate current drug discovery strategies. The dopamine hypothesis states that hyperactivity of the mesolimbic dopaminergic pathway is associated with positive symptoms of the disease, whereas hypoactivity of the mesocortical dopaminergic pathway is associated with the negative and cognitive symptoms. Increasing evidence has also suggested that hypoactivity in the corticolimbic glutamatergic system may contribute to the complex interplay between dysfunctional aspects of these neurotransmitter systems, which could account for much of the symptomatology observed in schizophrenia. Current antipsychotic drugs display moderate efficacy in treating the positive symptoms and limited efficacy against the negative, cognitive, or co-morbidity symptoms of the disease. They are also associated with significant side effects such as extrapyramidal side effects and metabolic disturbances. Thus pharmacologies that are able to more selectively modulate the underlying neuronal substrates of schizophrenia may have utility as efficacious and wide spectrum antipsychotic therapies with potentially improved side effect liabilities. The neuropeptide neuromodulator/neurotransmitter class and their associated receptors have been suggested to be one such family class. One such target which has shown particular promise, and thus has gained much pharmaceutical research interest, is the neurokinin receptor family and particularly the NK(3) receptor. The NK(3) receptor is expressed almost exclusively within the mammalian nervous system and its localisation is commensurate with a role in modulating central monoaminergic neurotransmission. Here we will provide an introduction to both the neurokinin ligands and receptors and review current preclinical understanding of their putative biological roles and, in particular, their modulatory role in the circuitry pertinent to schizophrenia. A brief review of the available chemical strategies employed to produce selective tools and drug development candidates will also be undertaken. Finally we will summarize the available clinical information on those compounds which have progressed into patient populations and evaluate their potential therapeutic utility, and the future of the NK(3) receptor target.
  Current pharmaceutical design 01/2010; 16(3):344-57. · 4.41 Impact Factor
• Article: The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2.

  Pier L D'Alessandro, Corrado Corti, Adelheid Roth, Annarosa Ugolini, Anna Sava, Dino Montanari, Federica Bianchi, Stephen L Garland, Ben Powney, Emma L Koppe, Magalie Rocheville, Greg Osborne, Paloma Perez, Jesús de la Fuente, Maite De Los Frailes, Paul W Smith, Clive Branch, David Nash, Stephen P Watson
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  ABSTRACT: The optimisation of an HTS hit series (1) leading to the identification of structurally novel, selective, orally bioavailable mGluR2 positive modulators GSK1331258 and GSK1331268 is described. Structure-activity relationships, attenuation of dopaminergic activity, and potentiation of mGluR2 responses in rat hippocampal MPP-DG synapses are also reported.
  Bioorganic & medicinal chemistry letters 11/2009; 20(2):759-62. · 2.65 Impact Factor
• Article: In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics.

  Lee A Dawson, Christopher J Langmead, Adeshola Dada, Jeannette M Watson, Zining Wu, Raúl de la Flor, Gareth A Jones, Jane E Cluderay, Eric Southam, Graham S Murkitt, Mark D Hill, Declan N C Jones, Ceri H Davies, Jim J Hagan, Paul W Smith
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  ABSTRACT: Clinical evaluation of tachykinin NK(3) receptor antagonists has provided support for the therapeutic utility of this target in schizophrenia. However, these studies have not been entirely conclusive, possibly because of the pharmacokinetic limitations of these molecules. In the search for tachykinin NK(3) receptor antagonists with improved properties, we have discovered GSK172981 and GSK256471. Both compounds demonstrated high affinity for recombinant human (pK(i) values 7.7 and 8.9, respectively) and native guinea pig (pK(i) values 7.8 and 8.4, respectively) tachykinin NK(3) receptors. In vitro functional evaluations revealed GSK172981 to be a competitive antagonist (pA(2)=7.2) at cloned human tachykinin NK(3) receptor whereas GSK256471 diminished the neurokinin B-induced E(max) response, indicative of non-surmountable antagonist pharmacology (pA(2)=9.2). GSK172981 also exhibited a competitive profile in antagonizing neurokinin B-stimulated neuronal activity recorded from the guinea pig medial habenula slices (apparent pK(B)=8.1), whilst GSK256471 abolished the agonist-induced response. Central nervous system penetration by GSK172981 and GSK256471 was indicated by dose-dependent ex vivo tachykinin NK(3) receptor occupancy in medial prefrontal cortex (ED(50) values of 0.8 and 0.9 mg/kg, i.p., respectively) and the dose-dependent attenuation of agonist-induced "wet dog shake" behaviours in guinea pigs. Finally, in vivo microdialysis studies demonstrated that acute GSK172981 (30 mg/kg, i.p.) and GSK256471 (1mg/kg, i.p.) attenuated haloperidol-induced increases in extracellular dopamine in the guinea pig nucleus accumbens. Taken together, these in vitro and in vivo characterisations of the tachykinin NK(3) receptor antagonists GSK172981 and GSK256471 support their potential utility in the treatment of schizophrenia.
  European journal of pharmacology 10/2009; 627(1-3):106-14. · 2.59 Impact Factor
• Article: New quinoline NK3 receptor antagonists with CNS activity.

  Paul W Smith, Paul A Wyman, Peter Lovell, Caroline Goodacre, Halina T Serafinowska, Antonio Vong, Frank Harrington, Sean Flynn, Daniel M Bradley, Rod Porter, Sara Coggon, Graham Murkitt, Kirsten Searle, David R Thomas, Jeannette M Watson, William Martin, Zining Wu, Lee A Dawson
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  ABSTRACT: Lead optimisation starting from the previously reported selective quinoline NK(3) receptor antagonists talnetant 2 (SB-223412) and 3 (SB-222200) led to the identification of 3-aminoquinoline NK(3) antagonist 10 (GSK172981) with excellent CNS penetration. Investigation of a structurally related series of sulfonamides with reduced lipophilicity led to the discovery of 20 (GSK256471). Both 10 and 20 are high affinity, potent NK(3) receptor antagonists which despite having different degrees of CNS penetration produced excellent NK(3) receptor occupancy in an ex vivo binding study in gerbil cortex.
  Bioorganic & medicinal chemistry letters 01/2009; 19(3):837-40. · 2.65 Impact Factor
• Article: Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands--part II.

  Simon E Ward, Peter Eddershaw, Sean T Flynn, Laurie Gordon, Peter J Lovell, Susan H Moore, Claire M Scott, Paul W Smith, Kevin M Thewlis, Paul A Wyman
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  ABSTRACT: A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
  Bioorganic & medicinal chemistry letters 12/2008; 19(2):428-32. · 2.65 Impact Factor
• Article: Novel 5-HT(1A/1B/1D) receptors antagonists with potent 5-HT reuptake inhibitory activity.

  Halina T Serafinowska, Frank E Blaney, Peter J Lovell, Giancarlo G Merlo, Claire M Scott, Paul W Smith, Kathryn R Starr, Jeannette M Watson
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  ABSTRACT: Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high affinities for the 5-HT(1A/1B/1D) receptors coupled with potent 5-HT reuptake inhibitory activity have been discovered. This is the first report describing docking of the lead compound 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-one 1, into a model of the 5-HT transporter and the 5-HT(1A) receptor model.
  Bioorganic & medicinal chemistry letters 10/2008; 18(20):5581-5. · 2.65 Impact Factor
• Article: Discovery of potent, orally bioavailable, selective 5-HT1A/B/D receptor antagonists.

  Simon E Ward, Peter J Eddershaw, Claire M Scott, Laurie J Gordon, Peter J Lovell, Susan H Moore, Paul W Smith, Kathryn R Starr, Kevin M Thewlis, Jeannette M Watson
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  ABSTRACT: 5-HT1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT1 receptor subtypes and providing new approaches for the treatment of depression.
  Journal of Medicinal Chemistry 06/2008; 51(10):2887-90. · 5.25 Impact Factor
• Article: Neurokinin 3 (NK3) receptor modulators for the treatment of psychiatric disorders.

  Paul W Smith, Lee A Dawson
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  ABSTRACT: The neurokinin-3 (NK(3)) is one of the tachykinin peptide neurotransmitter / neuromodulator receptor family. NK(3) receptors are predominantly expressed in neurons of both the peripheral and central nervous systems and in particular, in many of the forebrain areas, such as frontal, parietal and cingulate cortices, and basal ganglia structures implicated in psychiatric disease states. Consistent with this localization pattern, NK(3) receptors appear to modulate monoaminergic and amino acid neurotransmission within these structures. Taken together these observations have lead to the speculation that modulators of NK(3) receptor activity may have therapeutic utility in psychiatric diseases such as schizophrenia and affective disorders. This speculation has recently gained clinical credence through a number of reports of efficacy in placebo controlled studies. In this article, the authors review the recent patent literature highlighting the various NK(3) receptor modulation strategies for potential therapeutic utility in psychiatric disease indications.
  Recent Patents on CNS Drug Discovery 02/2008; 3(1):1-15.
• Article: Studies on a series of potent, orally bioavailable, 5-HT(1) receptor ligands.

  Simon E Ward, Christopher N Johnson, Peter J Lovell, Claire M Scott, Paul W Smith, Geoffrey Stemp, Kevin M Thewlis, Antonio K Vong, Jeannette M Watson
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  ABSTRACT: A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
  Bioorganic & Medicinal Chemistry Letters 10/2007; 17(18):5214-7. · 2.55 Impact Factor
• Article: 3,4-Dihydro-2H-benzoxazinones as dual-acting 5-HT1A receptor antagonists and serotonin reuptake inhibitors.

  Peter J Lovell, Frank E Blaney, Caroline J Goodacre, Claire M Scott, Paul W Smith, Kathryn R Starr, Kevin M Thewlis, Antonio K K Vong, Simon E Ward, Jeannette M Watson
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  ABSTRACT: Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.
  Bioorganic & Medicinal Chemistry Letters 03/2007; 17(4):1033-6. · 2.55 Impact Factor
• Article: Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.

  Robert J Young, Matthew Campbell, Alan D Borthwick, David Brown, Cynthia L Burns-Kurtis, Chuen Chan, Máire A Convery, Miriam C Crowe, Satish Dayal, Hawa Diallo, [......], Andrew M Mason, Jackie E Mordaunt, Champa Patel, Anthony J Pateman, Stefan Senger, Gita P Shah, Paul W Smith, Nigel S Watson, Helen E Weston, Ping Zhou
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  ABSTRACT: Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
  Bioorganic & Medicinal Chemistry Letters 01/2007; 16(23):5953-7. · 2.55 Impact Factor
• Article: SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'methyl-4'-(5-methyl-1,2,3-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): a novel, potent and selective 5-HT1B receptor antagonist.

  Claire Scott, Christopher J Langmead, Kirsten L Clarke, Paul Wyman, Paul W Smith, Kathryn R Starr, Lee A Dawson, Gary W Price, James J Hagan, Jeannette Watson
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  ABSTRACT: SB-616234-A possesses high affinity for human 5-HT1B receptors stably expressed in Chinese hamster ovary (CHO) cells (pKi 8.3+/-0.2), and is over 100-fold selective for a range of molecular targets except h5-HT1) receptors (pKi 6.6+/-0.1). Similarly, affinity (pKi) for rat and guinea pig striatal 5-HT1B receptors is 9.2+/-0.1. In [35S]-GTPgammaS binding studies in the human recombinant cell line, SB-616234-A acted as a high affinity antagonist with a pA2 value of 8.6+/-0.2 whilst providing no evidence of agonist activity in this system. In [35S]-GTPgammaS binding studies in rat striatal membranes, SB-616234-A acted as a high affinity antagonist with an apparent pKB of 8.4+/-0.5, again whilst providing no evidence of agonist activity in this system. SB-616234-A (1 microM) potentiated electrically stimulated [3H]-5-HT release from guinea pig and rat cortical slices (S2/S1) ratios of 1.8 and 1.6, respectively). SB-616234-A (0.3-30 mg kg(-1) p.o.) caused a dose-dependent inhibition of ex vivo [3H]-GR125743 binding to rat striatal 5-HT1B receptors with an ED50 of 2.83+/-0.39 mg kg(-1) p.o. Taken together these data suggest that SB-616234-A is a potent and selective 5-HT(1B) autoreceptor antagonist that occupies central 5-HT1B receptors in vivo following oral administration.
  Neuropharmacology 07/2006; 50(8):984-90. · 4.81 Impact Factor
• Article: Identification of a potent and selective 5-HT1B receptor antagonist.

  Paul A Wyman, Howard R Marshall, Sean T Flynn, Ron J King, Mervyn Thompson, Paul W Smith, Michael S Hadley, Gary W Price, Claire M Scott, Lee A Dawson
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  ABSTRACT: An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.
  Bioorganic & Medicinal Chemistry Letters 12/2005; 15(21):4708-12. · 2.55 Impact Factor