Kevin N Dack

Publications (9)17.07 Total impact

• Article: Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability.

  Patrick S Johnson, Thomas Ryckmans, Justin Bryans, Dave M Beal, Kevin N Dack, Neil Feeder, Anthony Harrison, Mark Lewis, Helen J Mason, James Mills, Julie Newman, Christelle Pasquinet, Dave J Rawson, Lee R Roberts, Rachel Russell, Deborah Spark, Alan Stobie, Toby J Underwood, Robin Ward, Simon Wheeler
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  ABSTRACT: The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.
  Bioorganic & medicinal chemistry letters 10/2011; 21(19):5684-7. · 2.65 Impact Factor
• Article: Acidic triazoles as soluble guanylate cyclase stimulators.

  Lee R Roberts, Paul A Bradley, Mark E Bunnage, Katherine S England, David Fairman, Yvette M Fobian, David N A Fox, Geoff E Gymer, Steven E Heasley, Jerome Molette, Graham L Smith, Michelle A Schmidt, Michael A Tones, Kevin N Dack
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  ABSTRACT: A series of acidic triazoles with activity as soluble guanylate cyclase stimulators is described. Incorporation of the CF(3) triazole improved the overall physicochemical and drug-like properties of the molecule and is exemplified by compound 25.
  Bioorganic & medicinal chemistry letters 08/2011; 21(21):6515-8. · 2.65 Impact Factor
• Article: Synthesis and evaluation of heteroarylalanine diacids as potent and selective neutral endopeptidase inhibitors.

  Melanie S Glossop, Richard J Bazin, Kevin N Dack, David N A Fox, Graeme A MacDonald, Mark Mills, Dafydd R Owen, Chris Phillips, Keith A Reeves, Tracy J Ringer, Ross S Strang, Christine A L Watson
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  ABSTRACT: Heteroarylalanine derivatives 4 were designed as potential inhibitors of neutral endopeptidase (NEP EC 3.4.24.11). Selectivity over other zinc metalloproteinases was explored through occupation of the S2' subsite within NEP. Structural optimisation led to the identification of 5-phenyl oxazole 4f, a potent and selective NEP inhibitor. A crystal structure of the inhibitor bound complex is reported.
  Bioorganic & medicinal chemistry letters 06/2011; 21(11):3404-6. · 2.65 Impact Factor
• Article: Optimisation of a pyrazole series of progesterone antagonists; Part 1.

  Kevin N Dack, Sarah Skerratt, Patrick S Johnson, Paul A Bradley, Ian R Marsh
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  ABSTRACT: The design and synthesis of a novel series of non-steroidal progesterone receptor antagonists is described. Ligand-lipophilicity efficiency (LLE) was used in the selection of a prototype agent for in vivo pharmacology studies.
  Bioorganic & medicinal chemistry letters 06/2010; 20(11):3384-6. · 2.65 Impact Factor
• Article: A novel series of highly selective inhibitors of MMP-3.

  Gavin A Whitlock, Kevin N Dack, Roger P Dickinson, Mark L Lewis
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  ABSTRACT: The design and synthesis of a series of highly selective hydroxamate inhibitors of stromelysin-1 (MMP-3) is described. Substitution of a 4-biaryl piperidine sulfonamide core, which binds at the S1' subsite of MMP-3, was optimised to give potent inhibitors of MMP-3, with greater than 300-fold selectivity over MMP-1, MMP-2, MMP-9 and MMP-14. Compounds 26 and 27 were identified as having the best balance of pharmacology and properties required for topical drug delivery.
  Bioorganic & medicinal chemistry letters 01/2008; 17(24):6750-3. · 2.65 Impact Factor
• Article: The Design and Synthesis of a Novel, Orally Active, Selective ETA Antagonist

  David J. Rawson, Kevin N. Dack, Roger P. Dickinson, Kim James, Clive Long, Don Walker
  Medicinal Chemistry Research 03/2004; 13(3):149-157. · 1.27 Impact Factor
• Article: The design and synthesis of a novel series of indole derived selective ET(A) antagonists.

  David J Rawson, Kevin N Dack, Roger P Dickinson, Kim James
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  ABSTRACT: Conformational constraint has been used as the key design element in the identification of a series of potent and selective ET(A) antagonists. The most potent antagonist, 32, (ET(A) IC(50)=0.55nM) is 722-fold selective over the ET(B) receptor, as measured by binding experiments.
  Bioorganic & Medicinal Chemistry Letters 02/2002; 12(2):125-8. · 2.55 Impact Factor
• Article: Thromboxane Modulating Agents. 3. 1 H -Imidazol-1-ylalkyl- and 3-Pyridinylalkyl-Substituted 3-[2-[(Arylsulfonyl)amino]ethyl]benzenepropanoic Acid Derivatives as Dual Thromboxane Synthase Inhibitor/Thromboxane Receptor Antagonists

  Roger P. Dickinson, Kevin N. Dack, Clive J. Long, John Steele
  Journal of Medicinal Chemistry - J MED CHEM. 01/1997; 40(21):3442-3452.
• Article: Thromboxane modulating agents. 2. Thromboxane receptor antagonists derived from the thromboxane synthase inhibitor dazmegrel.

  Roger P. Dickinson, Kevin N. Dack, John Steele, Michael S. Tute
  Bioorganic & Medicinal Chemistry Letters. 6(14):1691-1696.