Sorbitol-accumulating pyrimidine derivatives.

Abstract

The novel compounds SDI 157 (2-methyl-4(4-N,N-dimethylaminosulfonyl-1-piperazino)pyrimid ine, CAS 131816-54-1) and SDI 158 (2-hydroxymethyl-4-(4-N,N-dimethylaminosulfonyl-1- piperazino) pyrimidine, CAS 140687-51-0) have been found to be inhibitors of sorbitol dehydrogenase. In normal and diabetic animals both compounds induced a dose-dependent increase of tissue sorbitol, especially in the peripheral nerve, without alteration of the blood glucose. In contrast to SDI 158, SDI 157 does not act in vitro. However, in the isolated perfused rat liver SDI 157 induced a high sorbitol release and plasma samples of animals treated with SDI 157 induced a sorbitol accumulation in vitro in erythrocytes like SDI 158. SDI 157 seems to be a prodrug. In accordance with the polyol theory, the chronic administration of SDI 157 to diabetic rats accelerated the cataract development and depleted the lens of total and oxidized glutathione. Surprisingly, however, it accelerated the motor nerve conduction velocity in normal and diabetic rats, normalized the glomerular filtration rate in diabetic rats and did not induce retinal capillary lesions in normal rats or aggravate those in diabetic rats. At single oral doses up to 100 mg/kg, SDI 157, was well tolerated by diabetic and normal rats. Except for a reduction of drinking water consumption, the chronic administration of SDI 157 in drinking water at doses up to 100 mg/kg per day had no side effects in normal, diabetic and galactoselfructose-rich diet rats.