SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists

Bioorg Med Chem Lett. 2016 Mar 15;26(6):1529-1535. doi: 10.1016/j.bmcl.2016.02.022. Epub 2016 Feb 10.

Abstract

MK-4256, a tetrahydro-β-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-β-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.

Keywords: Antagonist; SAR; Somatostatin receptor subtype 3; Tetrahydro-β-carboline; hERG.

MeSH terms

  • Animals
  • Carbolines / chemical synthesis
  • Carbolines / chemistry*
  • Carbolines / pharmacology*
  • Dogs
  • Dose-Response Relationship, Drug
  • Humans
  • Mice
  • Molecular Structure
  • Rats
  • Receptors, Somatostatin / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Carbolines
  • MK-4256
  • Receptors, Somatostatin
  • somatostatin receptor 3