Journal of Medicinal Chemistry p. 4613 - 4627 (1992)
Update date:2022-08-04
Topics:
Wrobel, Jay
Dietrich, Arlene
Woolson, Shiela A.
Millen, Jane
McCaleb, Michael
et al.
Compounds from two novel series of spirosuccinimides were prepared.Analogs of series 2 possessed a spiro-fused isoindolone moiety while those of series 3 contained a spiro-fused benzisothiazole S,S-dioxide group.These compounds were evaluated as aldose reductase inhibitors (ARI) in vitro by their ability to inhibit glyceraldehyde reduction using a partially purified bovine lens aldose reductase preparation and in vivo as inhibitors of galactitol accumulation in the lens, sciatic nerve, and diaphragm of galactose-fed rats.Many members from the isoindolone series 2,particularly those containing an isoindolone N-methyl moiety, showed good in vitro and in vivo potency.The most potent member, the 6-chloro analog 32, was resolved, and aldose reductase activity was found to reside almost exclusively in the (+)-enantiomer.Compound 32 was approximately equipotent in the sciatic nerve of the galactose-fed rat to other cyclic imide ARI's of similar in vitro activity, namely sorbinil and ADN-138 and also to tolrestat, an acetic acid-based ARI (ED50's 4-8 mg/kg).Compounds from both series, 2 and 3, were also found to lower plasma glucose levels of genetically obese db/db and ob/ob mice with potency similar to that of ciglitazone.However, members from these series failed to lower insulin levels of the ob/ob mouse at the doses tested.
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