beta-Lactams have recently been identified as potent, highly efficacious cholesterol absorption inhibitors (CAIs). The discovery, SAR, and asymmetric synthesis of this class of hypolipidemic agents are described. Metabolism studies of the first clinical candidate, Sch 48461, led to the identification of a more potent second generation clinical candidate, Sch 58235 (ezetimibe) incorporating key structural elements of the active metabolites. A summary of preclinical and early clinical studies of ezetimibe as monotherapy and in combination with statins is also presented. Efforts to identify a pharmacophore model has led to the development of conformationally constrained analogs and analogs with conformational biases based on intramolecular hydrogen bonding possibilities. Finally, mechanism of action studies have led to the development of many biochemical tools for the investigation and identification of novel proteins involved in cholesterol uptake.

2003-04-01·British Journal of Pharmacology2区 · 医学

Ezetimibe potently inhibits cholesterol absorption but does not affect acute hepatic or intestinal cholesterol synthesis in rats

2区 · 医学

Article

作者: Margaret Van Heek ; Constance Farley ; April Smith-Torhan ; Lizbeth M Hoos ; Douglas S Compton ; Harry R Davis

Ezetimibe (1‐(4‐fluorophenyl)‐(3R)‐[3‐(4‐fluorophenyl)‐(3S)‐hydroxypropyl]‐(4S)‐(4‐hydroxyphenyl)‐2‐azetidinone) and its analog SCH48461 are potent and selective cholesterol absorption inhibitors that inhibit the transport of cholesterol across the intestinal wall, thereby lowering plasma cholesterol.

After a dose response for ezetimibe in rats was established, experiments were conducted to determine whether acute administration could alter hepatic or intestinal cholesterol synthesis. To determine whether this class of intestinal cholesterol absorption inhibitors could discriminate between newly synthesized cholesterol in the intestine versus exogenously administered cholesterol, rats were intraduodenally dosed with 14C‐cholesterol and 3H‐mevalonate, and mesenteric lymph was analyzed for radiolabeled cholesterol and cholesteryl ester content.

Ezetimibe attenuated diet‐induced hypercholesterolemia 60–94% at doses of 0.1–3 mg kg−1 in rats. A single administration of ezetimibe did not have a direct effect on intestinal or hepatic cholesterol synthesis, while ketoconazole significantly inhibited cholesterol synthesis after a single dose. The ezetimibe analog, SCH48461, inhibited the movement of exogenously administered cholesterol into lymph, but did not affect the appearance of newly synthesized cholesterol into lymph.

These data suggest that this class of cholesterol absorption inhibitors does discriminate by blocking the movement of exogenous cholesterol in the enterocyte before it reaches the intracellular cholesterol pool to be incorporated into intestinal lipoproteins, without affecting the incorporation of newly synthesized cholesterol into intestinal lipoproteins.

British Journal of Pharmacology (2003) 138, 1459–1464. doi:10.1038/sj.bjp.0705187

2002-11-01·Journal of Lipid Research2区 · 生物学

Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte

2区 · 生物学

Article

作者: Stephen D. Turley ; John M. Dietschy ; Joyce J. Repa

Intestinal cholesterol absorption is a major determinant of plasma low density lipoprotein-cholesterol (LDL-C) concentrations. Ezetimibe (SCH 58235) and its analogs SCH 48461 and SCH 58053 are novel potent inhibitors of cholesterol absorption whose mechanism of action is unknown. These studies investigated the effect of SCH 58053 on cholesterol metabolism in female 129/Sv mice. In mice fed a low cholesterol rodent diet containing SCH 58053, cholesterol absorption was reduced by 46% and fecal neutral sterol excretion was increased 67%, but biliary lipid composition and bile acid synthesis, pool size, and pool composition were unchanged. When the dietary cholesterol content was increased either 10- or 50-fold, those animals given SCH 58053 manifested lower hepatic and biliary cholesterol concentrations than did their untreated controls. Cholesterol feeding increased the relative mRNA level for adenosine triphosphate-binding cassette transporter A1 (ABCA1), ABC transporter G5 (ABCG5), and ABC transporter G8 (ABCG8) in the jejunum, and of ABCG5 and ABCG8 in the liver, but the magnitude of this increase was generally less if the mice were given SCH 58053. We conclude that the inhibition of cholesterol absorption effected by this new class of agents is not mediated via changes in either the size or composition of the intestinal bile acid pool, or the level of mRNA expression of proteins that facilitate cholesterol efflux from the enterocyte, but rather may involve disruption of the uptake of luminal sterol across the microvillus membrane.

100 项与 Sch-48461 相关的药物交易

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