Optimization of isochromanone based urotensin II receptor agonists

Research output: Contribution to journalArticle

Abstract

A series of novel isochromanone based urotensin II receptor agonists have been synthesized and evaluated for their activity using a functional cell based assay (R-SAT). Several potent and efficacious derivatives were identified with 3-(3,4-dichlorophenyl)-6,7-dimethyl-3-(2-dimethylaminoethyl)isochroman-1-one (28) being the most potent compound showing an EC50-value of 51 nM, thereby being the most potent compound so far within the isochromanone series. In addition, two other heterocyclic systems (isochromanes and tetrahydroisoquinolinones) were investigated and these derivatives were found to be both potent and efficacious. The activity of the isochromane derivatives implies that the carbonyl group of the isochromanone is not necessary for activity. Furthermore it was found that the geometry of the heterocycles was more important for receptor interaction than the composition of the heteroatoms present.

Details

Authors
  • Fredrik Lehmann
  • Erika A. Currier
  • Roger Olsson
  • Jian Nong Ma
  • Ethan S. Burstein
  • Uli Hacksell
  • Kristina Luthman
External organisations
  • University of Gothenburg
  • ACADIA Pharmaceuticals Inc.
  • ACADIA Pharmaceuticals AB
Research areas and keywords

Keywords

  • Agonist, GRP14, Isochromane, Isochromanone, SAR, Tetrahydroisoquinolinone, Urotensin II, UT-receptor
Original languageEnglish
Pages (from-to)4844-4854
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number13
Publication statusPublished - 2010 May 31
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes