The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues

J Med Chem. 2003 Oct 9;46(21):4533-42. doi: 10.1021/jm0300577.

Abstract

Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC(50) = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases / antagonists & inhibitors*
  • Animals
  • Blood Pressure / drug effects
  • Carbolines / chemical synthesis*
  • Carbolines / pharmacokinetics
  • Carbolines / pharmacology*
  • Cattle
  • Cyclic GMP / biosynthesis
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Drug Design
  • Hydantoins / chemical synthesis
  • Hydantoins / pharmacology
  • Indicators and Reagents
  • Isomerism
  • Models, Molecular
  • Molecular Conformation
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Phosphodiesterase Inhibitors / pharmacology*
  • Rats
  • Rats, Inbred SHR
  • Structure-Activity Relationship
  • Tadalafil

Substances

  • Carbolines
  • Hydantoins
  • Indicators and Reagents
  • Phosphodiesterase Inhibitors
  • Tadalafil
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Pde5a protein, rat
  • Cyclic GMP