1-Arylnaphthalene lignan: a novel scaffold for type 5 phosphodiesterase inhibitor

J Med Chem. 1999 Apr 8;42(7):1293-305. doi: 10.1021/jm9807048.

Abstract

1-Arylnaphthalene lignan, which had been reported as a PDE4 inhibitor by Iwasaki, was disclosed as a new structural class of PDE5 inhibitors. The structural requirements for potent and specific PDE5 inhibition were revealed in a 1-arylnaphthalene lignan series, in which 1-(3-bromo-4, 5-dimethoxyphenyl)-5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinylcarbon yl]-2-(methoxycarbonyl)naphthalene hydrochloride (27q) showed the most potent and specific inhibition (PDE5 inhibition IC50 = 6.2 nM, selectivity for PDE5 against PDE1, -2, -3, and -4 >16 000). It is noteworthy that 27q has the best selectivities against PDE isoforms among PDE5 inhibitors so far reported. Compound 27q exhibited almost the same relaxant effects on rat aortic rings as sodium 1-[6-chloro-4-[(3, 4-methylenedioxybenzyl)amino]quinazolin-2-yl]piperidine-4-ca rboxylate (35) (27q, EC50 = 0.10 microM; 35, EC50 = 0.20 microM) and was selected for further biological evaluation.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Animals
  • Aorta / drug effects
  • Cardiovascular Agents / chemical synthesis*
  • Cardiovascular Agents / chemistry
  • Cardiovascular Agents / pharmacology
  • Coronary Vessels / drug effects
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dogs
  • Heart / drug effects
  • In Vitro Techniques
  • Isoenzymes / antagonists & inhibitors
  • Lignans / chemistry*
  • Muscle Contraction / drug effects
  • Muscle Relaxation / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Myocardium / enzymology
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoric Diester Hydrolases / metabolism*
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Swine

Substances

  • 1-(3-bromo-4,5-dimethoxyphenyl)-5-chloro-3-(4-(2-hydroxyethyl)-1-piperazinylcarbonyl)-2-(methoxycarbonyl)naphthalene
  • Cardiovascular Agents
  • Isoenzymes
  • Lignans
  • Naphthalenes
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Pde5a protein, rat