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New quinoline NK3 receptor antagonists with CNS activity.

Authors
  • Smith, Paul W1
  • Wyman, Paul A
  • Lovell, Peter
  • Goodacre, Caroline
  • Serafinowska, Halina T
  • Vong, Antonio
  • Harrington, Frank
  • Flynn, Sean
  • Bradley, Daniel M
  • Porter, Rod
  • Coggon, Sara
  • Murkitt, Graham
  • Searle, Kirsten
  • Thomas, David R
  • Watson, Jeannette M
  • Martin, William
  • Wu, Zining
  • Dawson, Lee A
  • 1 Medicinal Chemistry, Neuroscience CEDD GlaxoSmithKline Research & Development, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. [email protected]
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Feb 01, 2009
Volume
19
Issue
3
Pages
837–840
Identifiers
DOI: 10.1016/j.bmcl.2008.12.005
PMID: 19117759
Source
Medline
License
Unknown

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.

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