Christine A L Watson

Publications (2)7.45 Total impact

• Article: Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.

  Paul A Glossop, Christine A L Watson, David A Price, Mark E Bunnage, Donald S Middleton, Anthony Wood, Kim James, Dannielle Roberts, Ross S Strang, Michael Yeadon, [......], Steven M Evans, Anthony C Harrison, David A Fairman, Balaji Agoram, Jane L Burrows, Neil Feeder, Craig K Fulton, Barry R Dillon, David A Entwistle, Fiona J Spence
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  ABSTRACT: A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.
  Journal of Medicinal Chemistry 08/2011; 54(19):6888-904. · 4.80 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