Leslie G. Humber

The medicinal chemistry of aldose reductase inhibitors

Publisher Summary This chapter discusses the medicinal chemistry of aldose reductase inhibitors. Insulin therapy has been dramatically effective in eliminating keto-acidotic coma as a cause of death in diabetics. While prolonging life, insulin therapy does not prevent the occurrence of disabling complications of chronic diabetes, such as neuropathy, nephropathy, retinopathy, and cataracts. Insulin therapy is only partially effective in normalizing glucose levels, and the occurrence of diabetic complications appears to be related to the severity and duration of diabetic hyperglycemia. The tissues involved (nerve, kidney, retina, and lens) do not require insulin for glucose uptake and consequently are exposed to elevated glucose levels. Under normal conditions, glucose is metabolized via the energy-producing glycolytic pathway involving an initial phosphorylation by the enzyme hexokinase. As a result, in the presence of high glucose concentrations, hexokinase becomes saturated, and the polyol pathway becomes activated, resulting in the intracellular production of sorbitol and fructose in tissues where this pathway exists.

Neuroleptic receptors: stereoselectivity for neuroleptic enantiomers.

In order to identify a pair of neuroleptic enantiomers with the highest stereoselective interaction with neuroleptic/dopamine receptors, the effects of eight pairs of neuroleptic enantiomers were tested on the specific binding of 3H-spiperone to crude homogenates of calf caudate nucleus. The ratios of the Ki values were: (+)-butaclamol/(-)-butaclamol = 3000; dexclamol/(-)-analogue = 151; (+)-isobutaclamol/(-)-isobutaclamol = 146; (-)-CTC/(+)-CTC= 109; (-)-centbutindole/(+)-centbutindole = 20; S(+)-octoclothepin/R(-)-octoclothepin = 11. Thus, the neuroleptic receptor is highly stereoselective for the rigid butaclamol derivatives, but much less so for the flexible neuroleptics. The 3H-apomorphine binding site, however, had a stereoselectivity ratio of only 7 for isobutaclamol, further suggesting that the high affinity sites (i.e. nM) for 3H-neuroleptic binding and for 3H-apomorphine binding are different.

The synthesis and structural characterization of way-120,491; a novel potassium channel activator

Abstract The synthesis of the antihypertensive potassium channel activator WAY-120,491 (1) is described. X-ray crystallographic analysis of carbamate 15a established the 3S,4R configuration of 1. The large scale classical resolution of racemic 9 was facilitated using authentic seed crystals, whose preparation was accomplished via novel coupling of racemic azidoalcohol 17 with the putative acyltriflate 20.