Aldose reductase inhibitors.
Aldose reductase ([EC1.1.1.21]: AR) acts on the first step of the polyol metabolic pathway to catalyze the reduction of glucose to sorbitol with NADPH as a coenzyme. Hyperactivity of the pathway in individuals with high blood glucose level is closely related to the onset or progression of diabetic complications. AR inhibitors have therefore been noted as possible pharmacotherapeutic agents for the treatment of diabetic complications. One AR inhibitor has been on the market in Japan, while some potent inhibitors are in clinical trials. Reviewed are the physiological roles of AR, the chemical structures of AR inhibitors, interactions of AR inhibitors with AR using X-ray studies, and the following potencies of AR inhibitors: in vitro activities for AR, in vitro selectivities between AR and aldehyde reductase, their pharmacological effects in vivo, and their effectiveness in clinical trials. Also discussed are directions for the design of future AR inhibitors.
Oka
M
M
Central Research Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan. m_oka@mb6.skk.net-net.com
Kato
N
N
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D002986:Clinical Trials as Topic; D018360:Crystallography, X-Ray; D003929:Diabetic Neuropathies / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D009281:Naphthalenes / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; D009281:Naphthalenes; D011799:Quinazolines; C040550:tolrestat; C064920:FR 74366; C077139:fidarestat; D000449:Aldehyde Reductase; C026411:sorbinil