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 (IC 50 ∼ 5 × 10 −7M). In a system in which sorbitol accumulation in isolated rat sciatic nerves was monitored in the presence of high (50 m M) glucose concentrations, CP-45,634 produced inhibition of polyol accumulation at levels as low as 1 × 10 −6M. 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 galactiol 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.