Decahydroisoquinoline derivatives as novel non-peptidic, potent and subtype-selective somatostatin sst(3) receptor antagonists

Bioorg Med Chem Lett. 2010 Mar 1;20(5):1728-34. doi: 10.1016/j.bmcl.2010.01.063. Epub 2010 Jan 21.

Abstract

Starting from non-peptidic sst(1)-selective somatostatin receptor antagonists, first compounds with mixed sst(1)/sst(3) affinity were identified by directed structural modifications. Systematic optimization of these initial leads afforded novel, enantiomerically pure, highly potent and sst(3)-subtype selective somatostatin antagonists based on a (4S,4aS,8aR)-decahydroisoquinoline-4-carboxylic acid core moiety. These compounds can efficiently be synthesized and show promising PK properties in rodents.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Humans
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacokinetics
  • Molecular Conformation
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Rats
  • Receptors, Somatostatin / antagonists & inhibitors*
  • Receptors, Somatostatin / genetics
  • Receptors, Somatostatin / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • (4-(3,4-difluorophenyl)-piperazine-1-yl)-(2-(3-(6-methoxypyridin- 3-yl)-2-methylpropyl)decahydroisoquinoline-4-yl)methanone
  • Isoquinolines
  • Protein Isoforms
  • Receptors, Somatostatin
  • Recombinant Proteins
  • isoquinoline