Potent, orally active aldose reductase inhibitors related to zopolrestat: surrogates for benzothiazole side chain

J Med Chem. 1992 Feb 7;35(3):457-65. doi: 10.1021/jm00081a006.


A broad structure-activity program was undertaken in search of effective surrogates for the key benzothiazole side chain of the potent aldose reductase inhibitor, zopolrestat (1). A structure-driven approach was pursued, which spanned exploration of three areas: (1) 5/6 fused heterocycles such as benzoxazole, benzothiophene, benzofuran, and imidazopyridine; (2) 5-membered heterocycles, including oxadiazole, oxazole, thiazole, and thiadiazole, with pendant aryl groups, and (3) thioanilide as a formal equivalent of benzothiazole. Several benzoxazole- and 1,2,4-oxadiazole-derived analogues were found to be potent inhibitors of aldose reductase from human placenta and were orally active in preventing sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic complications. 3,4-Dihydro-4-oxo-3-[(5,7-difluoro-2-benzoxazolyl)methyl]-1- phthalazineacetic acid (124) was the best of the benzoxazole series (IC50 = 3.2 x 10(-9) M); it suppressed accumulation of sorbitol in rat sciatic nerve by 78% at an oral dose of 10 mg/kg. Compound 139, 3,4-dihydro-4-oxo-3-[[(2-fluorophenyl)-1,2,4- oxadiazol-5-yl]methyl]-1-phthalazineacetic acid, with IC50 less than 1.0 x 10(-8) M, caused a 69% reduction in sorbitol accumulation in rat sciatic nerve at an oral dose of 25 mg/kg. The thioanilide side chain featured in 3-[2-[[3-(trifluoromethyl)phenyl]amino]-2-thioxoethyl]-3,4-dihydro - 4-oxo-1-phthalazineacetic acid (195) proved to be an effective surrogate for benzothiazole. Compound 195 was highly potent in vitro (IC50 = 5.2 x 10(-8) M) but did not show oral activity when tested at 100 mg/kg. Additional structure-activity relationships encompassing a variety of heterocyclic side chains are discussed.

MeSH terms

  • Administration, Oral
  • Aldehyde Reductase / antagonists & inhibitors*
  • Animals
  • Benzothiazoles
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / pharmacology*
  • Phthalazines / administration & dosage
  • Phthalazines / chemical synthesis
  • Phthalazines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Thiazoles / administration & dosage
  • Thiazoles / chemical synthesis
  • Thiazoles / pharmacology*


  • Benzothiazoles
  • Hypoglycemic Agents
  • Phthalazines
  • Thiazoles
  • zopolrestat
  • Aldehyde Reductase