We investigated the pharmacological profile of SMP-797, a novel hypocholesterolemic agent. SMP-797 showed inhibitory effects on acyl-coenzyme A: cholesterol acyltransferase (ACAT) activities in various microsomes and in human cell lines, and hypocholesterolemic effects in rabbits fed a cholesterol-rich diet and hamsters fed a normal diet. In hamsters, the reduction of total cholesterol level by SMP-797 was mainly due to the decrease of low-density lipoprotein (LDL) cholesterol level rather than that of very low-density lipoprotein (VLDL) cholesterol level. Interestingly, SMP-797 increased the hepatic low-density lipoprotein receptor expression in vivo when it decreased the low-density lipoprotein cholesterol level. SMP-797 also increased low-density lipoprotein receptor expression in HepG2 cells like atorvastatin, an HMG-CoA reductase inhibitor, although other acyl-coenzyme A: cholesterol acyltransferase inhibitor had no effect. In addition, SMP-797 had no effect on cholesterol synthesis in HepG2 cells. These results suggested that the increase of low-density lipoprotein receptor expression by SMP-797 was independent of its acyl-coenzyme A: cholesterol acyltransferase inhibitory action and did not result from the inhibition of hepatic cholesterol synthesis. In conclusion, these results suggest that SMP-797 is a novel hypocholesterolemic agent showing a cholesterol-lowering effect in which the increase of hepatic low-density lipoprotein receptor expression as well as the inhibition of acyl-coenzyme A: cholesterol acyltransferase is involved.
SummaryWe have developed a gastrointestinal hemorrhage model in mice and thereby assessed the potential risk of bleeding following administration of SM-20302, a nonpeptide GPIIb/IIIa receptor antagonist. First, SM-20302 selectively inhibited the interaction between human platelets and fibrinogen in vitro. Second, SM-20302 dose-dependently inhibited ADP-induced ex vivo platelet aggregation in mice and produced an ED50 value of 0.02 mg/kg. ED50 values of cyclo(RGDT)2, aspirin and ticlopidine were 0.48, 0.74 and 13.3 mg/kg, respectively. Finally, the bleeding risk of SM-20302 was examined in our newly developed hemorrhage model. Gastrointestinal hemorrhage was assessed 24 h later when the antiplatelet agents tested were administered to mice prior to the oral dosing of 0.1 N hydrochloric acid in 90% ethanol. The resulting hemorrhage was classified into three grades, major, minor or no bleeding, primarily based on the criteria used in the TIMI trial. All compounds tested induced gastrointestinal hemorrhage in a dose-dependent manner. Minimum hemorrhagic doses, MHDs, of SM-20302, cyclo (RGDT)2, aspirin and ticlopidine were 3, 3, 1 and 100 mg/kg, respectively. The potential risk of bleeding was assessed by the ratio of MHD to ED50 value. MHD/ED50 values of SM-20302, cyclo(RGDT)2, aspirin and ticlopidine were calculated to be 150, 6.3, 1.4 and 7.5, respectively. These results suggest that this experimental hemorrhage model may be useful for the evaluation of the bleeding complications of antiplatelet agents and that SM-20302 may have a wider therapeutic window than nonspecific integrin inhibitor and conventional antiplatelet agents.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.