Design and Development of Antisickling Compounds for the Treatment of Sickle Anemia

摘要

Three compounds-N-Acetyl-L-phenylalanine (NAP), N-phenylacetyl-L-Phenylalanine (PAP) and L-phenylalanyl-3-amino pyridine amide (PAPA) have exhibited antisickling activity at 30-33 mm Hg02 tension via visual and filterability assays. However, NAP displayed only marginal antisickling activity. Another facet of these compounds was their rapid rate of uptake by the erythrocyte and the resultant value of approximately 2 in their distribution ratios, extracellular to extracellular concentration. Permeability properties of NAP,PAP, and PAPA were found to have a large variation in their incorporation characteristics. The effect of intracellular concentration of PAP and PAPA is to increase the red cell volume. P02 affinity measurements on intact reds (normal and sickle) show a small shift to the right in the presence of 3.0 mM concentrations of PAP and PAPA. Crystallographic research efforts have resulted in a complete data set for PAP and PAPA. Toxicity studies on female and male mice scored for acute intraperitoneal toxicity showed that PAPA has moderate toxicity.