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Related Experiment Videos

Sorbitol-accumulating pyrimidine derivatives

K Geisen1, R Utz, H Grötsch

  • 1Hoechst Aktiengesellschaft, Frankfurt/Main, Fed. Rep. of Germany.

Arzneimittel-Forschung
|September 1, 1994
PubMed
Summary

Novel compounds SDI 157 and SDI 158 inhibit sorbitol dehydrogenase, increasing tissue sorbitol. Despite accelerating cataracts, SDI 157 improved nerve function and kidney filtration in diabetic rats, suggesting potential therapeutic benefits.

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Diabetology

Background:

  • Sorbitol dehydrogenase (SDH) inhibitors are explored for managing diabetic complications.
  • The polyol pathway plays a role in diabetic microvascular damage.

Purpose of the Study:

  • To investigate the effects of novel SDH inhibitors, SDI 157 and SDI 158, on sorbitol accumulation and diabetic complications.
  • To evaluate the in vivo and in vitro activity of SDI 157, identifying it as a potential prodrug.

Main Methods:

  • Administration of SDI 157 and SDI 158 to normal and diabetic animal models.
  • Measurement of tissue sorbitol levels, blood glucose, and glutathione.
  • Assessment of motor nerve conduction velocity, glomerular filtration rate, and retinal microvasculature.

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  • In vitro studies using isolated perfused rat liver and erythrocyte assays.

    • Main Results:

    • Both compounds increased tissue sorbitol, particularly in peripheral nerves, without affecting blood glucose.
    • SDI 157 demonstrated prodrug characteristics, showing in vivo activity but not in vitro.
    • Chronic SDI 157 administration accelerated cataract development but improved motor nerve conduction velocity and normalized glomerular filtration rate in diabetic rats.
    • SDI 157 was well-tolerated at tested doses and showed no adverse effects on retinal capillaries.

    Conclusions:

    • SDI 157 and SDI 158 effectively inhibit sorbitol dehydrogenase in vivo.
    • SDI 157 acts as a prodrug, offering potential therapeutic benefits for diabetic complications like neuropathy and nephropathy.
    • Further research is warranted to explore the therapeutic potential of SDI 157 despite its effect on cataract development.