Hypolipidemic Effect of a New Aryloxy Compound, S-8527, in Experimental Animals

Abstract

Abatract-The hypolipidemic action of 1,1-bis [4'-(l"-carboxy-1"-methylpropoxy)phenyl] cyclohexane (S-8527) was studied in rats, mice and rabbits under various ex perimental conditions to compare the effects with those of clofibrate. Oral ingestion of S-8527 to normal rats for 7 days lowered serum triglycerides and cholesterol by about 27% at 1 mg/kg and 20% at 3 mg/kg, respectively. The hypolipidemic effect of S-8527 was considered to be twenty to thirty times more potent than that of clo fibrate but a hepatomegalic effect of S-8527 was not observed at its effective dose ranging from 1 to 30 mg/kg. S-8527 at 3 mg/kg decreased liver triglyceride concen tration by about 20% but the decrease of triglyceride concentration was not ob served in clofibrate treated groups. Liver cholesterol concentration was not decreased with any of the doses of S-8527 while clofibrate decreased liver cholesterol concen tration by about 20% at 300 mg/kg. However, there were no differences in total content of cholesterol in liver between S-8527 and clofibrate treated groups. With Triton injected rats, a single oral dose of 100 mg/kg of S-8527 depressed the increase of serum triglycerides by about 50% while clofibrate did not. In glycerol-fed rats, S-8527 decreased serum and liver triglycerides more effectively than clofibrate, and in normal mice and cholesterol-fed mice, S-8527 was found to be more active than clo fibrate, however the hepatornegalic effect of S-8527 was less than that of clofibrate. Hypolipidemic effects in rabbits were not observed with either S-8527 or clofibrate.During a course of studies on hypolipidemic activity of various compounds synthe sized in our laboratory, we found that a new aryloxy compound, 1,1-bis [4'-(1 "-carboxy 1 "-methylpropoxy)phenyl] cyclohexane (S-8527) caused a marked decrease in serum lipids level at a smaller dose than that required for clofibrate and that there was a less hepatic effect at the effective dose in rats (1, 2). As studies concerning the dose-response relation ship in a wider range of doses of S-8527 were not included in the previous report (1), we do so herein.Recently, several new compounds of this class have been reported to show a lipid-low ering effect in rats and humans at a smaller dose than that required for clofibrate, but one of the general biological features of these compounds is that there is a marked hepatome galic effect in parallel with the hypolipidemic activity in the rodent (3-7).In the present study, an elucidation of the dose=response relationship for hypolipi demic activity of S-8527 in normal rats and its effect on hyperlipidemia induced by Triton injection, cholesterol feeding and glycerol loading in rats and mice are given. Hypolipidemic activity of S-8527 in normal mice and rabbits is also investigated.

Hypolipidemic drugs are inhibitors of phosphatidylcholine synthesis.

“…S-8527 decreases serum lipids in rodents (at 1 mg/kg per day) 20-30 times more effectively than does clofibrate (15,17,18) (19); it showed an IC50 of 1.7 mM and complete ChoPTase inhibition was attained at <5 mM (Fig. 1) Inhibition of LLAcylTase Activity.…”

“…4) Table 1). For example, SaH42-348 has been reported to be 8-9 times more effective than CPIB in decreasing serum lipids (9,10) whereas S-8527 (15)(16)(17)(18) and WY-14643 (12,38), particularly at low drug concentrations, were up to 180 times more effective than CPIB.…”

“…Clofibrate (ethyl p-chlorophenoxyisobutyrate) has been studied and used extensively (3)(4)(5), but less is known about the biochemical and physiological effects of various other hypolipidemic agents such as tibric acid [2-chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoicacid] (4,6-8), SaH-42-348f1-methyl-4-piperidyl bis-(p-chlorophenoxy)acetate] (9, 10), S-321328 [(4R)-4-(2,3,4,6,6ap,7,8,9,9aa,9b,-decahydro-6a/3-methyl- '3 -oxo-lH-cyclopenta[f]-quinolin-7,B3yl)valeric acid (11), WY-14643 ([4-chloro-(2,3-xylidino)-2-pyrimidinylthio]acetic acid) (4,(12)(13)(14), S-8527 (1,1-bis-[4'-(1"-carboxy-1"-methylpropoxy)phenyl]cyclohexane) (15)(16)(17)(18)(19), and DH-990 (2-[3,5-di-(t-butyl-4-hydroxyphenyl)thio]hexanoic acid) (4). The effectiveness of these agents generally has been attributed to their ability to interfere with certain phases of fatty acid (15,18,(20)(21)(22)(23), triglyceride (8,(23)(24)(25)(26)(27)(28)(29)(30)(31), and cholesterol (11,14,15,(32)(33)(34)(35)(36)(37)…”

Practical and Scalable Synthesis of 1,3-Adamantanediol

“…Nie and co-workers synthesized photosensitive resins with excellent etching resistance and heat resistance from 1,3-adamantanediol. Additionally, the bis-hydroxy functional groups give 1,3-adamantanediol an advantage in the preparation of polymers. − For example, Fu and co-workers synthesized a polycarbonate using 1,3-adamantanediol and diphenyl phosphoryl chloride, which is an effective halogen-free flame retardant. Zhenhua and co-workers introduced adamantane into the structure of polyimide, which can significantly improve its transparency and heat resistance.…”

Effects of S-8527 (1, 1-BIS [4’-(l”-Carboxy-L”-Methylpropoxy) Phenyl] Cyclohexane), A New Hypolipidemic Compound, on Platelet Aggregation, Adhesiveness and Blood Coagulation in Rats

“…cyclohexane) is about ten times more potent that that of elofibrate but the hepatomegalic effect of S-8527 is far less that that of clofibrate in rats (7)(8)(9)(10).…”