Reinhard Sarges

Aldose reductase inhibitors: recent developments

Perfect control of blood glucose levels in diabetic patients might ultimately be achieved with islet or pancreas transplants or with an artificial pancreas. However, to achieve such a goal on a large scale, it will be necessary to overcome the formidable safety or efficacy issues attendant with these approaches (see, e.g., [1, 2]). Meanwhile, in a substantial fraction of the estimated sixty million diabetic patients worldwide, current hypoglycemic therapy provides control of blood sugar levels that, in the long term, is inadequate. That is, current hypoglycemic therapy is still associated with substantial morbidity and mortality from the late microvascular complications of diabetes, principally diabetic neuropathy, retinopathy, and nephropathy. Attempts to achieve better long-term control of blood glucose through aggressive use of insulin and oral hypoglycemic agents, while yielding encouraging results, unfortunately have led to increased incidences of dangerous episodes of severe hypoglycemia.

Synthesis and aldose reductase inhibitory activity of substituted 2(1H)-benzimidazolone- and oxindole-1-acetic acids

Abstract Potent in vitro inhibition of the enzyme aldose reductase (AR) was observed with several members of a series of 3-alkylated 2(1 H )-benzimidazolone-1-acetic acids, as well as with analogs from a structurally-related series of oxindole-1-acetic acids with 3-alkyl or 3-alkylidene substituents. Intrinsic activity against AR was, in general, greatest in compounds from the second series, especially with analogs which contain alkylidene side chains, with typical IC 50 values of ≤ 1 μM. However, in a streptozotocin-diabetic rat model, the best compounds from either series failed to prevent sorbitol accumulation in lens or sciatic nerve to the degree observed with AR inhibitors such as ponalrestat or zopolrestat.

Sorbinil: A member of the novel class of spirohydantoin aldose reductase inhibitors☆

A decade ago, we discovered that spirohydantoins are a novel class of aldose reductase inhibitors characterized by very potent in vivo activity. This important discovery resulted from a systematic screening effort for in vitro activity against aldose reductase isolated from bovine lens and subsequent testing of active compounds for in vivo activity in a streptozotocin-diabetic rat model, measuring inhibition of sorbitol formation in sciatic nerve. In this in vivo model, spirohydantoins were clearly more potent than all known carboxylic acid-type aldose reductase inhibitors. Structure-activity studies in the spirohydantoin class demonstrated that potent in vitro and in vivo activity were obtained when the spiro junction was adjacent to an aromatic ring and when this junction was part of a 5- or 6-membered ring system fused to the aromatic ring. Excellent in vitro and in vivo activity was achieved in 6-halogenated chromane derivatives with the spirohydantoin group attached in the 4-position. In this series, biologic activity is highly stereospecific and associated with the S configuration. Sorbinil, the S isomer of the 6-fluoro derivative in this series, is one such example: it is 30 times more potent than its R isomer in vitro (IC50 0.15 v 4.4 mumol/L) and 100 times more potent in vivo (ED50 0.25 mg/kg po v 25 mg/kg po).