Lifibrol is a new lipid-lowering drug which lowers cholesterol to an extent in the order of magnitude of the statins. The mechanism of action of this compound is different from the one of statins but remains unknown. The current study will investigate the mechanism of action using stable-isotope turnover methods. The study will be done in healthy male volunteers.

Start Date01 Jan 1996

Sponsor / Collaborator

Universitätsklinikum Bonn

100 Clinical Results associated with Lifibrol

100 Translational Medicine associated with Lifibrol

100 Patents (Medical) associated with Lifibrol

Literatures (Medical) associated with Lifibrol

01 Dec 2010·Journal of Cardiovascular Pharmacology and TherapeuticsQ4 · MEDICINE

Lifibrol as a Model Compound for a Novel Lipid-Lowering Mechanism of Action

Q4 · MEDICINE

Article

Author: von Bergmann, Klaus ; Gouni-Berthold, Ioanna ; Berthold, Heiner K. ; Sudhop, Thomas

Lifibrol is a potent lipid-lowering drug with an unknown mechanism of action. We investigated its effects on lipoprotein and sterol metabolism in normocholesterolemic male participants. Seven participants were treated for 4 weeks with 600 mg/d lifibrol and 9 with 40 mg/d pravastatin in a double-blind randomized parallel-group trial. Kinetic studies were performed at baseline and under acute and chronic treatment. Turnover of apolipoprotein B-100 was investigated with endogenous stable-isotope labeling, and kinetic parameters were derived by multicompartmental modeling. Lathosterol and cholesterol metabolism were investigated using mass isotopomer distribution analysis (MIDA) after [1-13C]acetate labeling. Carbon metabolism was investigated by calculating the total isotope incorporation into newly formed sterols and measuring the disposal of acetate by 13CO2 breath analysis. Total- and low-density lipoprotein (LDL) cholesterol decreased by 18% and 27% under lifibrol and by 17% and 28% under pravastatin, respectively, whereas very-low-density lipoprotein (VLDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol did not change. Very-low-density lipoprotein apoB fractional synthesis and production increased under lifibrol but remained unchanged under pravastatin. Low-density lipoprotein apoB fractional synthesis and production increased under pravastatin but remained unchanged under lifibrol. Mass isotopomer distribution analysis indicated that both drugs decrease endogenous sterol synthesis after acute administration, but pravastatin had more powerful effects. Carbon-13 appearance in breath was higher during pravastatin than during lifibrol treatment. Mass isotopomer distribution analysis and carbon metabolism analysis indicated compartmentalization at the site of sterol synthesis, thus suggesting differential effects of the 2 drugs. Although having comparable lipid-lowering properties, lifibrol seems to have a mechanism of action distinct from that of statins. Lifibrol could serve as a model compound for the development of new lipid-lowering agents.

01 Nov 2003·Expert Opinion on PharmacotherapyQ3 · MEDICINE

Pharmacotherapy for dyslipidaemia – current therapies and future agents

Q3 · MEDICINE

Review

Author: Harold Bays ; Evan A Stein

Current lipid-altering agents that lower low density lipoprotein cholesterol (LDL-C) primarily through increased hepatic LDL receptor activity include statins, bile acid sequestrants/resins and cholesterol absorption inhibitors such as ezetimibe, plant stanols/sterols, polyphenols, as well as nutraceuticals such as oat bran, psyllium and soy proteins; those currently in development include newer statins, phytostanol analogues, squalene synthase inhibitors, bile acid transport inhibitors and SREBP cleavage-activating protein (SCAP) activating ligands. Other current agents that affect lipid metabolism include nicotinic acid (niacin), acipimox, high-dose fish oils, antioxidants and policosanol, whilst those in development include microsomal triglyceride transfer protein (MTP) inhibitors, acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, gemcabene, lifibrol, pantothenic acid analogues, nicotinic acid-receptor agonists, anti-inflammatory agents (such as Lp-PLA(2) antagonists and AGI1067) and functional oils. Current agents that affect nuclear receptors include PPAR-alpha and -gamma agonists, while in development are newer PPAR-alpha, -gamma and -delta agonists, as well as dual PPAR-alpha/gamma and 'pan' PPAR-alpha/gamma/delta agonists. Liver X receptor (LXR), farnesoid X receptor (FXR) and sterol-regulatory element binding protein (SREBP) are also nuclear receptor targets of investigational agents. Agents in development also may affect high density lipoprotein cholesterol (HDL-C) blood levels or flux and include cholesteryl ester transfer protein (CETP) inhibitors (such as torcetrapib), CETP vaccines, various HDL 'therapies' and upregulators of ATP-binding cassette transporter (ABC) A1, lecithin cholesterol acyltransferase (LCAT) and scavenger receptor class B Type 1 (SRB1), as well as synthetic apolipoprotein (Apo)E-related peptides. Fixed-dose combination lipid-altering drugs are currently available such as extended-release niacin/lovastatin, whilst atorvastatin/amlodipine, ezetimibe/simvastatin, atorvastatin/CETP inhibitor, statin/PPAR agonist, extended-release niacin/simvastatin and pravastatin/aspirin are under development. Finally, current and future lipid-altering drugs may include anti-obesity agents which could favourably affect lipid levels.

01 Nov 2000·AtherosclerosisQ2 · MEDICINE

The effects of lifibrol (K12.148) on the cholesterol metabolism of cultured cells: evidence for sterol independent stimulation of the LDL receptor pathway

Q2 · MEDICINE

Article

Author: Winfried März ; Michael Schliack ; Markus Nauck ; Heinrich Wieland ; Werner Groß ; Hedi Gierens ; Nikola Jeck ; Roland Löser ; Hubert Scharnagl

Lifibrol (4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) is a new hypocholesterolemic compound; it effectively lowers low density lipoprotein (LDL) cholesterol. We studied the effects of lifibrol on the cholesterol metabolism of cultured cells. In the hepatoma cell line HepG2, Lifibrol decreased the formation of sterols from [14C]-acetic acid by approximately 25%. Similar to lovastatin, lifibrol had no effect on the synthesis of sterols from [14C]-mevalonic acid. Lifibrol did not inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Instead, cholesterol synthesis inhibition by lifibrol was entirely accounted for by competitive inhibition of HMG-CoA synthase. Lifibrol enhanced the cellular binding, uptake, and degradation of LDL in cultured cells in a dose dependent fashion. The stimulation of LDL receptors was significantly stronger than expected from the effect of lifibrol on sterol synthesis. In parallel, lifibrol increased the amount of immunologically detectable receptor protein. Stimulation of LDL receptor mediated endocytosis was observed both in the presence and in the absence of cholesterol-containing lipoproteins. In the absence of an extracellular source of cholesterol, both lifibrol and lovastatin induced microsomal HMG-CoA reductase. Co-incubation with LDL was sufficient to suppress the lifibrol mediated increase in reductase activity, indicating that lifibrol does not affect the production of the non-sterol derivative(s) which are thought to regulate HMG-CoA reductase activity at the post-transcriptional level. Considered together, the data suggest that the hypolipidemic action of lifibrol may, at least in part, be mediated by sterol-independent stimulation of the LDL receptor pathway. A potential advantage of lifibrol is that therapeutic concentrations do not interfere with the production of mevalonate which is required not only to synthesize sterols but also as a precursor of electron transport moieties, glycoproteins and farnesylated proteins.

100 Deals associated with Lifibrol

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KEGG	Wiki	ATC	Drug Bank
D04737	-	-	DB12448

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Hypercholesterolemia	Phase 3	-	Merkle Pharmaceuticals	-
Hypercholesterolemia	Phase 3	-	Astellas Pharma, Inc.	-
Hypercholesterolemia	Phase 3	-	Astellas Pharma, Inc.	-
Hypercholesterolemia	Preclinical	-	Merkle Pharmaceuticals	-

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