Maureen Dempster

Publications (12)36.52 Total impact

• Article: Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity.

  Mark Baugh, Darcey Black, Paul Westwood, Emma Kinghorn, Kieran McGregor, John Bruin, William Hamilton, Maureen Dempster, Christopher Claxton, Jiaqiang Cai, [......], Clive Long, Heather McKinnon, Paul Vink, Leontien den Hoed, Monika Gorecka, Kalpit Vora, Ethan Grant, M David Percival, A Mieke H Boots, Marie-José van Lierop
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  ABSTRACT: The purpose of the study was to examine the potential of inhibition of cathepsin S as a treatment for autoimmune diseases. A highly selective cathepsin S inhibitor, CSI-75, was shown to upregulate levels of the cathepsin S substrate, invariant chain Lip10, in vitro as well as in vivo in C57Bl/6 mice after oral administration. Functional activity of the compound was shown by a reduction in the OVA-specific response of OVA-sensitized splenocytes from C57Bl/6 mice as well as from OVA-TCR transgenic mice (DO11.10). Since these studies revealed a selective suppression of the Th1 and Th17 cytokines causing a shift to Th2, CSI-75 was tested in the murine HC-gp39-immunization model. Indeed, CSI-75 specifically reduced the circulating HC-gp39-specific IgG2a in these mice indicating selective inhibition of the Th1 type of response in vivo. The importance of especially the Th1 and Th17 cell subsets in the pathology of autoimmune diseases, renders CatS inhibition a highly interesting potential therapeutic treatment of autoimmune diseases. Therefore, CSI-75 was tested in a murine model of multiple sclerosis (i.e. experimental autoimmune encephalomyelitis (EAE)) in a semi-therapeutic setting (ie. oral treatment after initial sensitization to antigen). Finally, in a murine model with features resembling rheumatoid arthritis (the collagen-induced arthritis (CIA) model), CSI-75 was tested in a therapeutic manner (after disease development). CSI-75 caused a significant reduction in disease score in both disease models, indicating a promising role for CatS inhibitors in the area of therapeutic treatments for autoimmune diseases.
  Journal of Autoimmunity 03/2011; 36(3-4):201-9. · 7.37 Impact Factor
• Article: 1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors: separation of desired cellular activity from undesired tissue accumulation through optimization of basic nitrogen pka.

  Wullie Arbuckle, Mark Baugh, Simone Belshaw, D Jonathan Bennett, John Bruin, Jiaqiang Cai, Kenneth S Cameron, Chris Claxton, Maureen Dempster, Kathryn Everett, Xavier Fradera, William Hamilton, Philip S Jones, Emma Kinghorn, Clive Long, Iain Martin, John Robinson, Paul Westwood
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  ABSTRACT: Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pk(a) of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pk(a) 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.
  Bioorganic & medicinal chemistry letters 02/2011; 21(3):932-5. · 2.65 Impact Factor
• Article: Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists.

  Ronald Palin, Lynn Abernethy, Nasrin Ansari, Kenneth Cameron, Tom Clarkson, Maureen Dempster, David Dunn, Anna-Marie Easson, Darren Edwards, John Maclean, [......], Lesley-Anne Nisbet, Michael Ohlmeyer, Quynhchi Pham, Paul Ratcliffe, Yajing Rong, Andrew Roughton, Melanie Sammons, Robert Swanson, Heather Tracey, Glenn Walker
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  ABSTRACT: Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
  Bioorganic & medicinal chemistry letters 02/2011; 21(3):892-8. · 2.65 Impact Factor
• Article: Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles.

  Paul Ratcliffe, Lynn Abernethy, Nasrin Ansari, Ken Cameron, Tom Clarkson, Maureen Dempster, David Dunn, Anna-Marie Easson, Darren Edwards, Katy Everett, [......], Lesley-Anne Nisbet, Michael Ohlmeyer, Ronnie Palin, Quynhchi Pham, Yajing Rong, Andrew Roughton, Melanie Sammons, Robert Swanson, Heather Tracey, Glenn Walker
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  ABSTRACT: Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.
  Bioorganic & medicinal chemistry letters 01/2011; 21(15):4652-7. · 2.65 Impact Factor
• Article: Identification of potent, soluble, and orally active TRPV1 antagonists.

  Paul Ratcliffe, John Maclean, Lynn Abernethy, Tom Clarkson, Maureen Dempster, Anna-Marie Easson, Darren Edwards, Katy Everett, Helen Feilden, Peter Littlewood, Duncan McArthur, Deborah McGregor, Hazel McLuskey, Olaf Nimz, Lesley-Anne Nisbet, Ronnie Palin, Heather Tracey, Glenn Walker
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  ABSTRACT: Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration.
  Bioorganic & medicinal chemistry letters 01/2011; 21(8):2559-63. · 2.65 Impact Factor
• Article: Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.

  Zoran Rankovic, Jiaqiang Cai, Jennifer Kerr, Xavier Fradera, John Robinson, Ashvin Mistry, William Finlay, George McGarry, Fiona Andrews, Wilson Caulfield, [......], Phil Jones, Joost C M Uitdehaag, Mario van Zeeland, Dominique Potin, Laurent Saniere, Andre Fouquet, François Chevallier, Hortense Deronzier, Cecile Dorleans, Eric Nicolai
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  ABSTRACT: Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.
  Bioorganic & medicinal chemistry letters 11/2010; 20(21):6237-41. · 2.65 Impact Factor
• Article: Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors.

  Jiaqiang Cai, John Robinson, Simone Belshaw, Kathryn Everett, Xavier Fradera, Mario van Zeeland, Leon van Berkom, Peter van Rijnsbergen, Lucy Popplestone, Mark Baugh, [......], Paul Westwood, Jennifer Kerr, Zoran Rankovic, Wullie Arbuckle, D Jonathan Bennett, Philip S Jones, Clive Long, Iain Martin, Joost C M Uitdehaag, Tommi Meulemans
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  ABSTRACT: The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.
  Bioorganic & medicinal chemistry letters 10/2010; 20(23):6890-4. · 2.65 Impact Factor
• Article: 4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important.

  Jiaqiang Cai, Xavier Fradera, Mario van Zeeland, Maureen Dempster, Kenneth S Cameron, D Jonathan Bennett, John Robinson, Lucy Popplestone, Mark Baugh, Paul Westwood, John Bruin, William Hamilton, Emma Kinghorn, Clive Long, Joost C M Uitdehaag
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  ABSTRACT: Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.
  Bioorganic & medicinal chemistry letters 08/2010; 20(15):4507-10. · 2.65 Impact Factor
• Article: 6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors.

  Jiaqiang Cai, Mark Baugh, Darcey Black, Clive Long, D Jonathan Bennett, Maureen Dempster, Xavier Fradera, Jonathan Gillespie, Fiona Andrews, Sylviane Boucharens, [......], Zoran Rankovic, John Robinson, Paul Scullion, Joost C M Uitdehaag, Paul Vink, Paul Westwood, Mario van Zeeland, Leon van Berkom, Martijn Bastiani, Tommi Meulemans
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  ABSTRACT: 6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.
  Bioorganic & medicinal chemistry letters 08/2010; 20(15):4350-4. · 2.65 Impact Factor
• Article: 2-Phenyl-9H-purine-6-carbonitrile derivatives as selective cathepsin S inhibitors.

  Jiaqiang Cai, D Jonathan Bennett, Zoran Rankovic, Maureen Dempster, Xavier Fradera, Jonathan Gillespie, Iain Cumming, William Finlay, Mark Baugh, Sylviane Boucharens, [......], Paul Scullion, Joost C M Uitdehaag, Mario van Zeeland, Dominique Potin, Laurent Saniere, Andre Fouquet, Francois Chevallier, Hortense Deronzier, Cecile Dorleans, Eric Nicolai
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  ABSTRACT: Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors.
  Bioorganic & medicinal chemistry letters 08/2010; 20(15):4447-50. · 2.65 Impact Factor
• Article: Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors.

  Zoran Rankovic, Jiaqiang Cai, Jennifer Kerr, Xavier Fradera, John Robinson, Ashvin Mistry, Emma Hamilton, George McGarry, Fiona Andrews, Wilson Caulfield, [......], William Hamilton, Joost Uitdehaag, Mario van Zeeland, Dominique Potin, Laurent Saniere, Andre Fouquet, François Chevallier, Hortense Deronzier, Cecile Dorleans, Eric Nicolai
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  ABSTRACT: Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.
  Bioorganic & medicinal chemistry letters 01/2010; 20(5):1524-7. · 2.65 Impact Factor
• Article: Dioxo-triazines as a novel series of cathepsin K inhibitors.

  Zoran Rankovic, Jiaqiang Cai, Xavier Fradera, Maureen Dempster, Ashvin Mistry, Ann Mitchell, Clive Long, Emma Hamilton, Angela King, Sylviane Boucharens, Craig Jamieson, Jonathan Gillespie, Iain Cumming, Joost Uitdehaag, Mario van Zeeland
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  ABSTRACT: A novel dioxo-triazine series of cathepsin K inhibitors was identified from HTS. A rapid exploratory programme led to the discovery of potent and selective cathepsin K inhibitors, typified by compound 24 which displayed IC(50) values of 17nM against catK and >10,000nM in catL, catB and catS assays.
  Bioorganic & medicinal chemistry letters 01/2010; 20(5):1488-90. · 2.65 Impact Factor