Cooh

Tolrestat

Fig. 29. Chemical structure of some aldose reductase inhibitors.

activity, only about half a dozen showed sufficient aldose reductase-inhibiting activity and acceptable toxicity in vivo and in man.

Apart from ad hoc designed compounds, a number of natural products and their derivatives, predominantly heterocyclic alkanoic acids, are known to inhibit aldose reductase. These are rhodanine derivatives (Tadeo et al., 1982), quinolineacetic acid derivatives (Poulsom and Heath, 1983), phthalazinoneacetic acid (Stribling et al., 1983), furanopropionic acid and synthetic analogues (Okamoto et al., 1984), coumarin-4-acetic acid derivatives (Sarges et al., 1980), benzopyran- and benzothiopyran-carboxylic acids (Belletire, 1980), and a number of natural and synthetic flavones. This wide variety of compounds is representative of the chemical heterogeneity of such inhibitors. Nevertheless, a chromone ring system is common to all aldose reductase inhibitors.

Recent chemical developments are: (1) tetramethyleneglutaric acid (AY-20,037) (Ayerst); (2) alrestatin (Ayerst) (Fig. 29); (3) tolrestat (Ayerst) (Fig. 29); (4) epalrestat (Ono); (5) sorbinil (Pfizer) (Fig. 29); (6) ponalrestat (ICI-128,436) (ICI).

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