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Spiro hydantoin aldose reductase inhibitors
R Sarges1, R C Schnur, J L Belletire
1Pfizer Central Research, Groton, Connecticut 06340.
Journal of Medicinal Chemistry
|January 1, 1988
Summary
Aldose reductase inhibitors, like sorbinil, show promise in treating diabetic complications by blocking harmful sorbitol formation. The spiro hydantoin sorbinil is a potent inhibitor currently undergoing human trials for diabetic neuropathy.
Area of Science:
- Biochemistry
- Pharmacology
- Diabetology
Background:
- Sorbitol accumulation, catalyzed by aldose reductase, is implicated in diabetic complications.
- Aldose reductase enzyme activity is a key target for therapeutic intervention in diabetes.
Purpose of the Study:
- To identify and evaluate spiro hydantoin compounds as aldose reductase inhibitors.
- To assess the in vivo efficacy of these inhibitors in preventing sorbitol formation.
Main Methods:
- Inhibition of isolated calf lens aldose reductase by spiro hydantoins.
- In vivo assessment of sorbinil's effect on sciatic nerve sorbitol levels in diabetic rats.
- Stereochemical analysis of aldose reductase inhibition.
Main Results:
- Spiro hydantoins effectively inhibit aldose reductase and reduce in vivo sorbitol formation.
- Optimal activity was observed with spiro hydantoins derived from 6-halogenated 4-chromanones.
- The 4S isomer of 2,4-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione (sorbinil) demonstrated exclusive inhibitory activity.
Conclusions:
- Spiro hydantoins are potent aldose reductase inhibitors with therapeutic potential for diabetic complications.
- Sorbinil (CP-45,634) is a highly effective inhibitor and is being investigated in human clinical trials for diabetic neuropathy treatment.