Pharmacological profile of F 12511, (S)-2 ',3 ',5 '-trimethyl-4 '-hydroxy-alpha-dodecylthioacetanilide a powerful and systemic acylcoenzyme A: cholesterol acyltransferase inhibitor

The pharmacological profile of F 12511 (S)-2',3',5'-trimethyl-4'-hydroxy-al pha -dodecylthio-phenylacetanilide, a new inhibitor of acyl-CoA: cholestero l acyltransferase (EC 2.3.1.26; ACAT), was evaluated by using different in vitro and in vivo models. In vitro, F 12511 was shown to be a highly potent inhibitor of ACAT activity in microsomal preparations from various animal species as well as of cholesterol esterification in relevant human cell lin es in culture. The concentrations of F 12511 required to produce 50% inhibi tion of ACAT activity (IC50 values) in microsomal preparations ranged from 41nM for hypercholesterolemic rabbit intestine to 223 nM for normocholester olemic hamster liver. In whole cell assays using hepatic (Hep G2), intestin al (CaCo-2) and macrophagic (THP-1) cell lines, F 12511 inhibited ACAT acti vity with IC50 values of 3, 7, and 71 nM, respectively. In vivo, orally adm inistered F 12511 displayed high potency and efficacy as an antihypercholes terolemic compound in different cholesterol-fed animals (rat, guinea-pig, r abbit). For instance, in guinea-pigs the dose required to reduce plasma cho lesterol levels by 30% (ED30 value) was 0.008 mg.kg(-1). In rabbits, an ani mal species prone to atherosclerosis, the hypocholesterolemic effect was ac companied by a dose-related reduction in the incidence of aortic fatty stre aks that reached asymptote at 2.5 mg.kg(-1) and by an improvement of the im paired endothelial function. When given orally to chow-fed hamsters, F 1251 1 elicited a dose-related decrease in plasma cholesterol from 9% at 0.63 mg .kg(-1) up to 31% at 40 mg.kg(-1) associated with a preferential reduction in atherogenic lipoproteins, very low density lipoproteins (VLDL) and low d ensity lipoproteins (LDL). Moreover, in the same dose range, F 12511 decrea sed hepatic cholesteryl ester concentrations and reduced liver ex vivo ACAT activity. By using a bioassay, ACAT inhibitory activity was present in pla sma of treated hamsters 1 hr after oral administration of F 12511. Hence, t he results in chow-fed hamsters are consistent with systemic and direct hep atic effects of F 12511. In guinea-pigs, an adreno-sensitive species, F 125 11 did not impair the adrenal function (adrenocorticotrophic hormone challe nge) at doses up to 2.5 mg.kg(-1). far higher than those eliciting hypochol esterolemic effects in the same species. In conclusion, the results suggest that F 12511, a powerful and systemic ACAT inhibitor, constitutes an appro priate tool to determine whether the inhibition of ACAT constitutes an effe ctive therapy for the treatment of hypercholesterolemia and of atherosclero sis in man. (C) 2000 Elsevier Science Inc. All rights reserved.