Renal medullary cells contain high levels of (glycine) betaine, glycerophosphorylcholine (GPC), myo-inositol, and sorbitol. Two functions of these have been proposed: 1) that they are compatible osmolytes which regulate cell volume (against high external NaCl) without inhibiting proteins and 2) that methylamines (GPC and betaine) are counteracting osmolytes which stabilize proteins against perturbation from high renal urea. As a test of the latter, osmolyte contents in kidney medullas were measured in rats subjected to three types of dietary manipulation: 1) diets with protein and NaCl contents varied oppositely, 2) diets with a constant low NaCl and varied protein content, and 3) a low-calorie diet. With low-protein and low-calorie diets, only renal contents of urea, GPC, and inositol decreased; betaine and sorbitol contents increased such that contents of total nonurea organic osmolytes remained constant. With high-protein diets, only renal contents of sodium, urea, and GPC increased, with the latter giving total organic osmolytes a consistent correlation to sodium. Across all diets, the only consistent (linear) correlations were 1) between urea and GPC contents, supporting previous suggestions that GPC is the major counteractant to urea, and 2) between total organic osmolytes and sodium (but not urea) contents, as predicted by the compatible osmolytes hypothesis.
Fourteen new 4-substituted 2,4-dioxobutanoic acids have been synthesized. These compounds, all of which contain lipophilic 4-substituents, are potent inhibitors in vitro of porcine liver glycolic acid oxidase. The I50 value of the two most potent representatives, 4-(4'-bromo[1,1'-biphenyl]-4-yl)-2, 4-dioxobutanoic acid (8) and 4-[4'-[[(3,4-dihydro-3-hydroxy-2H-1, 5-benzodioxepin-3-yl)methyl]thio][1,1'-biphenyl]-4-yl]-2, 4-dioxobutanoic acid (13) is 6 X 10(-8)M.
An extensive series of novel 4-substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives has been prepared and studied as inhibitors of glycolic acid oxidase (GAO). Compounds possessing large lipophilic 4-substituents are, in general, potent, competitive inhibitors of porcine liver GAO in vitro. Methylation of the nitrogen or the 3-hydroxy substituent reduced potency dramatically, indicating the requirement for the two acidic functions on the 1H-pyrrole-2,5-dione nucleus. In rat liver perfusion studies, with three representative compounds, concentration-dependent inhibition of the conversion of [1-14C]glycolate to [14C]oxalate was observed. Chronic oral administration to ethylene glycol fed rats of the 4-(4'-bromo[1,1'-biphenyl]-4-yl) derivative (83) was shown to effect a significant reduction in urinary oxalate levels over a 58-day period.
The enzyme glycolic acid oxidase oxidizes glycolate to glyoxylate and glyoxylate to oxalate. Three series of compounds related to the natural substrates, substituted glycolic, oxyacetic, and glyoxylic acids, have been investigated as inhibitors of this enzyme using the techniques of regression analysis and quantitative structure-activity relationships. The best overall correlation with inhibitory potencies was found with the Hansch hydrophobic parameter pi. The classical electronic parameters sigmap, sigmam, F, and R performed poorly. For the substituted glyoxylic acids, a dummy parameter relating to the presence of a nucleophilic group in close proximity to the alpha-carbonyl of the glyoxylate group was found to be highly significant. The syntheses of six novel glycolic and glyoxylic acids are described.
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