4-(3-Chloro-4-methoxybenzyl)aminophthalazines: synthesis and inhibitory activity toward phosphodiesterase 5

J Med Chem. 2000 Jun 29;43(13):2523-9. doi: 10.1021/jm9905054.

Abstract

We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthala zinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC(50) = 0.56 nM) with >1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC(50) = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 microg/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / pharmacokinetics
  • Antihypertensive Agents / pharmacology
  • Biological Availability
  • Blood Pressure / drug effects
  • Coronary Vessels / drug effects
  • Coronary Vessels / physiology
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dinoprost / pharmacology
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / physiopathology
  • In Vitro Techniques
  • Male
  • Muscle Relaxation / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Phosphodiesterase Inhibitors / chemical synthesis*
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoric Diester Hydrolases / metabolism*
  • Phthalazines / chemical synthesis*
  • Phthalazines / chemistry
  • Phthalazines / pharmacokinetics
  • Phthalazines / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology
  • Quinazolines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Swine
  • Vasodilator Agents / chemical synthesis*
  • Vasodilator Agents / chemistry
  • Vasodilator Agents / pharmacokinetics
  • Vasodilator Agents / pharmacology

Substances

  • (4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino)-6-phthalazinecarbonitrile
  • Antihypertensive Agents
  • E 4021
  • Phosphodiesterase Inhibitors
  • Phthalazines
  • Piperidines
  • Quinazolines
  • Vasodilator Agents
  • Dinoprost
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Pde5a protein, rat