title: CP-45,634: a novel aldose reductase inhibitor that inhibits polyol pathway activity in diabetic and galactosemic rats.
abstract: In some tissues containing aldose reductase, increased flux through the polyol pathway has been implicated as being causative in diabetic complications (e.g., cataracts, peripheral neuropathy). We have found CP-45,634 (d-6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione) to be a highly potent, structurally novel, uncompetitive inhibitor of calf lens aldose reductase (IC50 approximately 5 X 10(-7)M). In a system in which sorbitol accumulation in isolated rat sciatic nerves was monitored in the presence of high (50 mM) glucose concentrations, CP-45,634 produced inhibition of polyol accumulation at levels as low as 1 X 10(-6)M. To determine if in vitro activity would translate to in vivo models, sorbitol accumulation in rat sciatic nerves was measured 27 hr after induction of diabetes with streptozotocin. Orally administered CP-45,634 was effective at dose levels as low as 0.25 mg/kg, t.i.d., and at 0.75 mg/kg produced an 85% inhibition of sorbitol accumulation. Two weeks after induction of diabetes by streptozotocin, sorbitol levels in rat lens and the sciatic nerve rose to 21,203 nmole/gm and 1,161 nmole/gm, respectively. Subsequent oral administration of CP-45,634 (2.5 mg/kg, b.i.d.) for 1 wk reduced these levels by 92% in nerves and 90% in lenses. In galactosemic rats, CP-45,634 inhibited the rise in lens galactitol and effectively delayed cataract formation at oral doses as low as 5 mg/kg/day. These high levels of in vivo activity suggest that CP-45,634 has potential for assessing the role of the polyol pathway in diabetic complications.
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002386:Cataract / Q000139:chemically induced / Q000517:prevention & control; D002839:Chromans / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004376:Galactitol / Q000378:metabolism; D005690:Galactose; D005693:Galactosemias / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007700:Kinetics; D007908:Lens, Crystalline / Q000378:metabolism; D008297:Male; D011108:Polymers / Q000378:metabolism*; D051381:Rats; D012584:Sciatic Nerve / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
chemical_list: D001578:Benzopyrans; D002839:Chromans; D007093:Imidazoles; D048289:Imidazolidines; D011108:Polymers; C024617:polyol; D004376:Galactitol; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; C026411:sorbinil; D005690:Galactose