Syntheses of tolrestat analogues containing additional substituents in the ring and their evaluation as aldose reductase inhibitors. Identification of potent, orally active 2-fluoro derivatives

J Med Chem. 1991 Aug;34(8):2504-20. doi: 10.1021/jm00112a029.


A series of aldose reductase inhibitors were prepared which were analogues of the potent, orally active inhibitor tolrestat (1). These compounds (5, 7, 9, and 10) have an extra substituent on one of the unoccupied positions on the naphthalene ring of 1. Primary amide prodrugs of several members from the series 5 and 7, namely 6 and 8, respectively, were also prepared. These compounds were evaluated in two in vitro systems: an isolated enzyme preparation from bovine lens to assess their intrinsic inhibitory activity and an isolated sciatic nerve assay to determine their ability to penetrate membranes of nerve tissue. These compounds were also evaluated in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats. In general, compounds in series 5, 7, 9, and 10 were potent inhibitors of bovine lens aldose reductase. 2-Halo-substituted analogues from the series 5, 7, and 9 exhibited high activity in the nerve of the 4-day-galactose-fed rat, and in several instances, the primary amide prodrug 8 enhanced the in vivo potency of the respective carboxylic acid 7. Two 2-fluoro-derivatives, 8a and 9a, had especially high activity in vivo and were chosen for additional studies. These compounds were found to be approximately equipotent to tolrestat in the sciatic nerve of the galactose-fed rat and the STZ rat, as judged by their ED50's in these assays. Although primary amide analogue 8a did not have intrinsic inhibitory activity toward aldose reductase, it was metabolized to an active form in vivo and also in vitro within the sciatic nerve.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Aldehyde Reductase / antagonists & inhibitors*
  • Animals
  • Cattle
  • Chemical Phenomena
  • Chemistry
  • Diabetes Mellitus, Experimental / enzymology
  • Diaphragm / enzymology
  • Galactitol / metabolism
  • Galactose / metabolism
  • Glycine / analogs & derivatives
  • Glycine / chemical synthesis
  • Glycine / pharmacology
  • Lens, Crystalline / enzymology
  • Male
  • Molecular Structure
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry*
  • Naphthalenes / pharmacology
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Sciatic Nerve / enzymology


  • Naphthalenes
  • Prodrugs
  • tolrestat
  • Galactitol
  • N-((2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl)carbonyl)-N-(methoxycarbonyl)glycine
  • N-((aminocarbonyl)methyl)-2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide
  • Aldehyde Reductase
  • Glycine
  • Galactose