Synthesis and biological activities of novel beta-carbolines as PDE5 inhibitors

Bioorg Med Chem Lett. 2003 Feb 24;13(4):761-5. doi: 10.1016/s0960-894x(02)01036-3.

Abstract

A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
  • Animals
  • Blood Pressure / drug effects
  • Carbolines / chemical synthesis*
  • Carbolines / pharmacology*
  • Combinatorial Chemistry Techniques / methods
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dogs
  • Drug Evaluation, Preclinical
  • Erectile Dysfunction / drug therapy
  • Humans
  • Isoenzymes
  • Male
  • Penis / drug effects
  • Piperazines
  • Purines
  • Sildenafil Citrate
  • Solubility
  • Structure-Activity Relationship
  • Sulfones

Substances

  • Carbolines
  • Isoenzymes
  • Piperazines
  • Purines
  • Sulfones
  • Sildenafil Citrate
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human