Hypolipidaemic properties of a potent and bioavailable alkylsulphinyl-diphenylimidazole ACAT inhibitor (RP 73163) in animals fed diets low in cholesterol

Q2 · MEDICINE

Article

Author: Neil V. Harris ; Raymond C. Bush ; David P. Parrott ; Christopher Smith ; Una M. Moore ; Kuni Naik ; David Hele ; Robert J. Williams ; Brenda J. Burton ; David Riddell ; Colin P. Bright

RP 73163 ((S)-2-[5-(3,5-dimethyl-l-pyrazolyl)pent-l-yl)-sulphinyl]-5, 6-diphenylimidazole) has been shown to be a potent and specific inhibitor of acyl-CoA:cholesterol acyltransferase (EC 2.3.1.26; ACAT) in vitro using the tissues of experimental animals as sources of the enzyme. The concentrations of RP 73163 required to produce 50% inhibition of ACAT activity (IC50 values) in microsomal preparations ranged from 86 nM for rat liver to 370 nM for rabbit intestine. In whole cell assays using human hepatic (HepG2), intestinal (Caco2), and monocytic (THP-1) cell lines, RP 73163 inhibited ACAT activity with IC50 values of 266, 158, and 314 nM, respectively. The addition of RP 73163 (0.03-1.0 microM) to the medium of cultured HepG2 cells produced a concentration-dependent decrease in apolipoprotein B (apoB) secretion. The compound has high systemic bioavailability. Using a bioassay, a concentration of active inhibitor equivalent to 29 microM of parent compound was present in plasma 1 hr after oral administration of RP 73163 (50 mg.kg-1). In rats that had been fed a basal diet ad libitum or starved for 18 hr prior to blood sampling, the administration of RP 73163 (50 mg.kg-1 b.i.d. for 7 days) reduced plasma triglyceride levels by 50% without affecting the concentration of cholesterol. This hypotriglyceridaemic effect was associated with reductions in plasma very-low-density-lipoprotein (VLDL) and low-density-lipoprotein (LDL) levels. RP 73163 decreased the rate of VLDL secretion by 24% in Triton WR-1339-treated rats that had been fasted overnight but did not affect the secretion rate in animals fed ad libitum, indicating that ACAT was only important in regulating VLDL secretion under certain nutritional conditions. RP 73163 reduced the accumulation of intraperitoneally administered [3H]leucine into the plasma VLDL-apoB pool in both fed and fasted states. The results suggest that, in fed animals at least, an increase in the clearance of VLDL from the bloodstream may contribute to the hypolipidaemic activity of the compound. In rabbits with casein-induced endogenous hypercholesterolaemia, RP 73163 specifically reduced the levels of cholesterol carried by LDL. In conclusion, the hypolipidaemic actions of RP 73163, a potent and systemically bioavailable ACAT inhibitor, are consistent with a reduction in the secretion of apoB containing lipoproteins by hepatic tissue and possibly with an increase in the clearance of these particles.

01 Nov 1994·Journal of Chromatography B: Biomedical Sciences and Applications

Assay and single dose pharmacokinetics of a novel systemic acyl coenzyme A cholesterol O-acyltransferase inhibitor, RP 73163, in rat plasma using automated solid-phase extraction with high-performance liquid chromatography

Article

Author: Trudy A. Hoff ; Graham D. Jones ; Pravin B. Chauhan ; Paul E. Gunraj ; Vincenzo Facchini

RP 73163, (S)-2-[5-(3,5-dimethylpyrazol-1-yl)pent-1-yl]sulphinyl-4,5 diphenylimidazole (I), is a highly potent in vitro and in vivo inhibitor of acyl coenzyme A cholesterol O-acyltransferase (ACAT) (E.C. 2.3.1.26), and as such it has potential therapeutic use as a cholesterol lowering agent in man. A method has been developed for the extraction and assay of I from rat plasma, using a fully automated solid-phase extraction column (ASPEC) technique, coupled to a reversed-phase HPLC system with detection by native fluorescence. The method has been validated over the concentration range 10-500 ng/ml, with demonstrated linearity, precision and accuracy, the mean limit of detection being 6.6 +/- 1.3 ng/ml. Application of the method to the assay of samples following administration of the compound to male and female rats is reported, together with determined pharmacokinetic parameters.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Discovery	FR	Rhone-Poulenc SA	-

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