4-Benzylamino-1-chloro-6-substituted phthalazines: synthesis and inhibitory activity toward phosphodiesterase 5

J Med Chem. 1998 Aug 27;41(18):3367-72. doi: 10.1021/jm970815r.

Abstract

We synthesized various 4-benzylamino-1-chloro-6-substituted phthalazines (15) and 4-benzylamino-1-chloro-7-substituted phthalazines (16) and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) purified from porcine platelets. The PDE5-inhibitory activities of 15 were greater than those of the isomers (16). The preferred substituent at the 4-position of phthalazine was a (3-chloro-4-methoxybenzyl)amino group, and those at the 6-position were cyano, nitro, and trifluoromethyl groups. Compounds 15a (IC50 = 4.8 nM), 15f (3.5 nM), and 15i (5.3 nM) were more potent inhibitors than E4021 (8.6 nM). Compounds 15a and 15f also showed vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The EC50 values for vasorelaxant action of 15a, 15f, and E4021 were 150, 160, and 980 nM, respectively. These results show that novel PDE5 inhibitors possessing a potent vasorelaxant effect may exist among phthalazine derivatives.

Publication types

  • Comparative Study

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Animals
  • Blood Platelets / enzymology
  • Coronary Vessels / drug effects
  • Coronary Vessels / physiology
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Dinoprost / pharmacology
  • In Vitro Techniques
  • Muscle Contraction / drug effects
  • Muscle Relaxation / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Phosphodiesterase Inhibitors* / chemical synthesis
  • Phosphodiesterase Inhibitors* / pharmacology
  • Phosphoric Diester Hydrolases / metabolism*
  • Phthalazines* / chemical synthesis
  • Phthalazines* / chemistry
  • Phthalazines* / pharmacology
  • Piperidines / pharmacology
  • Quinazolines / pharmacology
  • Swine
  • Vasodilator Agents* / chemical synthesis
  • Vasodilator Agents* / pharmacology

Substances

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