Effects of a Novel Potent Aldose Reductase Inhibitor, GP : 1447, on Aldose Reductase Activity In Vitro and on Diabetic Neuropathy and Cataract Formation in Rats

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Author(s)

    • AKAIKE Nobuhide
    • Pharmaceutical Research Laboratories, Research Center, Research and Development Division, Grelan Pharmaceutical Co., Ltd.
    • OHBAYASHI Shigeo
    • Pharmaceutical Research Laboratories, Research Center, Research and Development Division, Grelan Pharmaceutical Co., Ltd.
    • AOTSUKA Tomoji
    • Pharmaceutical Research Laboratories, Research Center, Research and Development Division, Grelan Pharmaceutical Co., Ltd.
    • ABE Naoki
    • Pharmaceutical Research Laboratories, Research Center, Research and Development Division, Grelan Pharmaceutical Co., Ltd.
    • FUKUSHIMA Kanako
    • Pharmaceutical Research Laboratories, Research Center, Research and Development Division, Grelan Pharmaceutical Co., Ltd.
    • MATSUURA Akihiro
    • Pharmaceutical Research Laboratories, Research Center, Research and Development Division, Grelan Pharmaceutical Co., Ltd.

Abstract

GP-1447 {3-[(4, 5, 7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenylacetic acid}, a novel aldose reductase (AR)inhibitor, exhibited highly potent and specific inhibition of AR activity from human placenta, human muscle, porcine and rat lens with IC<SUB>50</SUB> values ranging from 3 to 10 nM. Lineweaver-Burk plots revealed non-competitive inhibition between DL-glyceraldehyde or β-NADPH and inhibition of AR by GP-1447. In contrast to epalrestat, AR activity inhibited by GP-1447 did not recover after dialysis for 24 hr. Administration of GP-1447 to streptozotocin (STZ)-induced diabetic rats for 5 days beginning 1 week after STZ injection effectively inhibited the accumulation of sorbitol in the sciatic nerve, lens and retina with ED<SUB>50</SUB> values of 0.25, 1.6 and 2.9 mg/kg/day, respectively. The motor nerve conduction velocity (MCV)in STZ-induced diabetic rats was significantly decreased 4 weeks after the induction of diabetes. Treatment with GP-1447 for the following 2 weeks dose-dependently restored the decreased MCV with an ED<SUB>50</SUB> value of 0.28 mg/kg/day. Administration of GP-1447 (3 and 15 mg/kg/day for 12 weeks beginning 3 days after STZ injection)completely prevented cataract formation and was accompanied by marked inhibition of sorbitol accumulation in the lens. Furthermore, partial reversibility of cataract formation and morphological changes of the lens was observed in diabetic rats treated with 15 mg/kg/day of GP-1447 for 5 weeks beginning 8 weeks after the induction of diabetes. From these results, GP-1447 would be expected to exert potent ameliorating effects on some diabetic complications. Potent inhibition of cataract formation will be one of the characteristics of this compound.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 73(2), 133-144, 1997-02-01

    The Japanese Pharmacological Society

References:  37

Cited by:  6

Codes

  • NII Article ID (NAID)
    10008677107
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    00215198
  • NDL Article ID
    4153688
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  CJPref  NDL  J-STAGE 
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