Epalrestat

Development of (Z, )-5-(2-methyl-3-phenyl-2-propenylidene)4-oxo-2-thio-xothiazolidine-3-acetic acid (Epalrestat, Kinedak), an aldose reductase inhibitor 97YGK651. 

Aldose reductase inhibitors (SEDA-19, 397 SEDA-20, 399 SEDA-21, 447 SEDA-22, 477) have been developed for the treatment of secondary complications in diabetes (1,2). They include alrestatin, benurestat, epalrestat, fidarestat, imirestat, lidorestat, minalrestat, ponalrestat, ranirestat, risarestat, sorbinil, tolrestat, zenarestat, and zopolrestat (all rINNs). 

Several potent AR inhibitors have been developed which, structurally, are heterocyclic alkanoic acids. Of a large series of rhodanine derivatives [88, 89], ( )-3-carboxymethyl-5-[(2 )-methyl-3-phenylpropenylidene]rhodanine (ONO-62235 epalrestat, 26) has been selected for clinical development. Epal-restat has an IC50 value of 1 x 10 8 M with AR from rat lens and an IC50 of 2.6 x 10 " 6 M with human placental AR [90]. Another series of rhodanines has been reported, the most potent of which was the aminomethylidene derivative (27), which had an IC50 value of 2.3 x 10 " 8 M with rat lens AR [91]. No in vivo results were presented. 

The kinetics of AR inhibition by several inhibitors have been studied the flavonoids quercitrin [28] and axillarin [29], as well as sulindac [111], alrestatin [28], indomethacin [111], and -bromophenylsulphonylhydantoin [84], have been shown to be noncompetitive inhibitors. In addition, epalrestat [90], sorbinil [113, 114], TMG [115], 7-hydroxy-4-oxo-4//-chromene-6-car-boxylic acid [32] and statil [95] were found to exhibit mixed uncompetitive-noncompetitive inhibition. Hence, these and other AR inhibitors [116] do not compete for the substrate-binding site on the enzyme. Furthermore, other studies show that various AR inhibitors do not compete for the nucleotide-cofactor-binding site [114,116]. 

DG levels in diabetic patients [81], Furthermore, fidarestat, epalrestat and ranirestat [82] have been tested in patients with diabetic neuropathy, with improvement in nerve function. Ranirestat is currently being studied in a Phase 3 clinical trial in patients with diabetic sensorimotor polyneuropathy. 

Epalrestat inhibits the enzyme aldose reductase, which converts glucose to sorbitol. The accumulation of sorbitol may play a role in some diabetic complications. 

Oral antidiabetics Aldose reductase inhibitors Epalrestat... 

In comparison, 1-naphthyl-substituted derivatives were more potent inhibitors (IC5Q= 10 nM) with similar activity to epalrestat. 4-Oxo-2-thioxo-5-(2-naphthylmethylene)-3-thiazolidine-acetic acids were obtained by the condensation of substrate 4 with appropriate 2-naphthaldehydes. Results of in vitro studies related to these two classes of compounds are represented in Table 9.3 [16]. 

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