Design and synthesis of novel 5-(3,4,5-trimethoxybenzoyl)-4-aminopyrimidine derivatives as potent and selective phosphodiesterase 5 inhibitors: scaffold hopping using a pseudo-ring by intramolecular hydrogen bond formation

Bioorg Med Chem Lett. 2014 Nov 15;24(22):5175-80. doi: 10.1016/j.bmcl.2014.09.082. Epub 2014 Oct 2.

Abstract

5-(3,4,5-Trimethoxybenzoyl)-4-amimopyrimidine derivatives were found as a novel chemical class of potent and highly selective phosphodiesterase 5 inhibitors. A pseudo-ring formed by an intramolecular hydrogen bond constrained the conformation of 3-chloro-4-methoxybenzylamino and 3,4,5-trimethoxybenzoyl substituents and led to the discovery of T-6932 (19a) with a potent PDE5 inhibitory activity (IC50 = 0.13 nM) and a high selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2400). Further modification at the 2-position of T-6932 resulted in the finding of 26, which exhibited potent relaxant effects on isolated rabbit corpus cavernosum (EC30 = 11 nM) with a high PDE5 selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2800).

Keywords: Erectile dysfunction; Intramolecular hydrogen bond; PDE5; PDE6; Pseudo-ring.

MeSH terms

  • Animals
  • Cattle
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / antagonists & inhibitors
  • Dogs
  • Drug Design*
  • Humans
  • Hydrogen Bonding
  • Phosphodiesterase 5 Inhibitors / chemical synthesis*
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology
  • Rabbits

Substances

  • Phosphodiesterase 5 Inhibitors
  • Pyrimidines
  • 4-aminopyrimidine
  • Cyclic Nucleotide Phosphodiesterases, Type 6