The design and synthesis of potent, selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists with an increased barrier of atropisomerization

Bioorg Med Chem. 2012 May 1;20(9):2845-9. doi: 10.1016/j.bmc.2012.03.029. Epub 2012 Mar 24.

Abstract

Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective bombesin receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725(1) Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature.

MeSH terms

  • Animals
  • Benzodiazepines / chemistry*
  • Drug Design*
  • Humans
  • Mice
  • Protein Binding
  • Rats
  • Receptors, Bombesin / agonists*
  • Receptors, Bombesin / metabolism
  • Stereoisomerism
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacokinetics
  • Temperature

Substances

  • Receptors, Bombesin
  • Sulfonamides
  • bombesin receptor subtype 3
  • Benzodiazepines