2. Academic Validation
  3. New quinoline NK3 receptor antagonists with CNS activity

New quinoline NK3 receptor antagonists with CNS activity

  • Bioorg Med Chem Lett. 2009 Feb 1;19(3):837-40. doi: 10.1016/j.bmcl.2008.12.005.
Paul W Smith 1,  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
Affiliations

Affiliation

  • 1 Medicinal Chemistry, Neuroscience CEDD GlaxoSmithKline Research & Development, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Paul.W.Smith@GSK.com
PMID: 19117759 DOI: 10.1016/j.bmcl.2008.12.005
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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