Highly potent 4-amino-indolo[2,3-c]azepin-3-one-containing somatostatin mimetics with a range of sst receptor selectivities

J Med Chem. 2009 Jan 8;52(1):95-104. doi: 10.1021/jm801205x.

Abstract

The synthesis, biological evaluation, and conformational analysis of 4-amino-indolo[2,3-c]azepin-3-one (Aia)-containing SRIF mimetics are reported. Different subtype selectivities are observed depending on the N- and C-terminal substituents of the D-Aia-Lys dipeptide mimetic. An sst(5)-selective analogue with subnanomolar binding affinity was obtained that is the most potent agonist reported to date. A nonselective mimetic with high potency was also identified. This study allows a better definition of the bioactive conformation of the essential D-Trp side chain in the somatostatin pharmacophore.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry*
  • Animals
  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Azepines / metabolism*
  • Biomimetic Materials / chemical synthesis
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / metabolism
  • Cell Line
  • Cricetinae
  • Humans
  • Indoles / chemistry*
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Peptides / metabolism
  • Receptors, Somatostatin / metabolism*
  • Somatostatin / chemistry*
  • Somatostatin / metabolism*
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Amines
  • Azepines
  • Indoles
  • Peptides
  • Receptors, Somatostatin
  • Somatostatin