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.

• Ashizawa Naoki

  Pharmaceutical Research Laboratories, Research Center, Research and Development Division, Grelan Pharmaceutical Co., Ltd.

• Yoshida Motoyuki

  Pharmaceutical Research Laboratories, Research Center, Research and Development Division, Grelan Pharmaceutical Co., Ltd.

• Sugiyama Yoshiko

  Pharmaceutical Research Laboratories, Research Center, Research and Development Division, Grelan Pharmaceutical Co., Ltd.

• 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.

Bibliographic Information

Other Title

• Effects of a Novel Potent Aldose Reduct

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 IC₅₀ 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 ED₅₀ 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 ED₅₀ 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

  The Japanese Pharmacological Society

Keywords

• Aldose reductase inhibitor
• Sorbitol
• Diabetic neuropathy
• Motor nerve conduction velocity
• Cataract formation

Details

• CRID: 1390282679263672320
• NII Article ID: 10008677107
• NII Book ID: AA00691188
• DOI: 10.1254/jjp.73.133
• COI: 1:CAS:528:DyaK2sXhsVWnsro%3D
• ISSN: 13473506
• ISSN: 00215198
• ISSN: http://id.crossref.org/issn/00215198
• NDL BIB ID: 4153688
• PubMed: 9074947
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I4153688
• Web Site: https://search.jamas.or.jp/link/ui/1997123111
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
• Abstract License Flag: Disallowed