Synthesis and pharmacological evaluation of optically pure, novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists

Bioorg Med Chem. 2014 Nov 1;22(21):6026-38. doi: 10.1016/j.bmc.2014.09.005. Epub 2014 Sep 16.

Abstract

A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT(2B) and 5-HT(7) receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4',5'-dihydro-3'H-spiro[fluorene-9,2'-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT(2B) (Ki = 5.1 nM) and 5-HT(7) (K(i) = 1.7 nM) receptors with high selectivity over 5-HT(2A), 5-HT(2C), α(1), D(2) and M(1) receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.

Keywords: 5-HT(2B) receptor; 5-HT(7) receptor; Dual antagonist; Migraine; Optical resolution.

MeSH terms

  • Animals
  • CHO Cells
  • Cricetulus
  • Guinea Pigs
  • HEK293 Cells
  • Humans
  • Molecular Docking Simulation
  • Receptor, Serotonin, 5-HT2B / metabolism*
  • Receptors, Serotonin / metabolism*
  • Serotonin 5-HT2 Receptor Antagonists / chemical synthesis
  • Serotonin 5-HT2 Receptor Antagonists / chemistry
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology
  • Serotonin Antagonists / chemical synthesis
  • Serotonin Antagonists / chemistry*
  • Serotonin Antagonists / pharmacology*

Substances

  • Receptor, Serotonin, 5-HT2B
  • Receptors, Serotonin
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • serotonin 7 receptor