Delving into the Latest Updates on LY-518674 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

PPARα

Mechanism

PPARα agonists(Peroxisome proliferator-activated receptor α agonists)

Therapeutic Areas

Cardiovascular DiseasesEndocrinology and Metabolic Disease

Active Indication-

Inactive Indication

AtherosclerosisHypercholesterolemiaHypertension+ [2]

Originator Organization

Ligand Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

Eli Lilly & Co.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC23H27N3O4

InChIKeyPNHFDVSKDSLUFH-UHFFFAOYSA-N

CAS Registry425671-29-0

Agents that increase HDL-C via reverse cholesterol transport could provide a new therapeutic option for the prevention of atherosclerotic cardiovascular disease. The investigators propose to investigate the effects of LY518674 on components that may likely affect atherogenesis in patients with the metabolic syndrome including HDL-C metabolism and reverse cholesterol transport pathways, the inflammatory response, and oxidative stress in human subjects.
As an agonist of the nuclear peroxisome proliferator activated receptor (PPAR) alpha, LY518674 may affect the transcription of genes that encode various proteins involved in atherogenesis. This study will explore the consequences of altered transcription such as changes in messenger ribonucleic acid (mRNA) and protein levels as well as protein activity.

Start Date01 Jan 2006

Sponsor / Collaborator

University of Pennsylvania

[+1]

100 Clinical Results associated with LY-518674

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100 Translational Medicine associated with LY-518674

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100 Patents (Medical) associated with LY-518674

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13

Literatures (Medical) associated with LY-518674

01 Nov 2015·European Heart JournalQ1 · MEDICINE

Potent peroxisome proliferator-activated receptor- agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome

Q1 · MEDICINE

Article

Author: Rader, Daniel J ; Khera, Amit V ; Millar, John S ; Ruotolo, Giacomo ; Wang, Ming-Dauh

AIMSFibrate medications weakly stimulate the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α) and are currently employed clinically in patients with dyslipidaemia. The potent and selective agonist of PPAR-α LY518674 is known to substantially increase apolipoprotein A-I (apoA-I) turnover without major impact on steady-state levels of apoA-I or high-density lipoprotein-cholesterol (HDL-C). We sought to determine whether therapy with a PPAR-α agonist impacts cholesterol efflux capacity, a marker of HDL function.METHODS AND RESULTSCholesterol efflux capacity was measured at baseline and after 8 weeks of therapy in a randomized, placebo-controlled trial involving participants with metabolic syndrome treated with either LY518674 100 μg daily (n = 13) or placebo (n = 15). Efflux capacity assessment was quantified using a previously validated ex vivo assay that measures the ability of apolipoprotein-B depleted plasma to mobilize cholesterol from macrophages. LY518674 led to a 15.7% increase from baseline (95% CI 3.3-28.1%; P = 0.02, P vs. placebo = 0.01) in efflux capacity. The change in apoA-I production rate in the active treatment arm was strongly linked to change in cholesterol efflux capacity (r = 0.67, P = 0.01).CONCLUSIONSPotent stimulation of PPAR-α leads to accelerated turnover of apoA-I and an increase in cholesterol efflux capacity in metabolic syndrome patients despite no change in HDL-C or apoA-I levels. This finding reinforces the notion that changes in HDL-C levels may poorly predict impact on functionality and thus has implications for ongoing pharmacologic efforts to enhance apoA-I metabolism.

01 May 2010·AtherosclerosisQ2 · MEDICINE

The effect of PPAR-α agonism on apolipoprotein metabolism in humans

Q2 · MEDICINE

Review

Author: Daniel J. Rader ; John S. Millar ; Ashish Shah

Metabolic syndrome, diabetes and obesity are frequently associated with hypertriglyceridemia, hypercholesterolemia and low HDL levels, a phenotype known as atherogenic dyslipidemia. Atherogenic dyslipidemia and hypertriglyceridemia are frequently treated with fibric acid derivatives which activate the nuclear receptor PPAR-alpha leading to reduce plasma triglycerides and an increase in HDL cholesterol levels. The mechanism by which activation of PPAR-alpha with fibrates improves the plasma lipid profile in patients with atherogenic dyslipidemia and hypertriglyceridemia has been examined in several small studies measuring lipoprotein kinetics. The results of these studies indicate that the changes in lipoprotein metabolism observed in response to fibrate treatment vary according to lipoprotein phenotype. In general, fibrates act to reduce VLDL apoB-100 through enhanced fractional catabolism (clearance) of VLDL apoB-100 with additional effects on reducing VLDL apoB-100 production. LDL apoB-100 levels generally decrease in response to fibrates due to increased LDL fractional catabolism except in those patients with high to very high plasma triglyceride levels (>400mg/dL). Fibrates also increase HDL apoA-I and apoA-II levels by enhancing apoA-I and apoA-II production, although this is partially counteracted by increasing fractional catabolism of these apolipoproteins. The potent and specific PPAR-alpha agonist LY518674, reduced VLDL apoB-100 levels through enhanced fractional catabolism similar to what is seen with fibrates. In contrast to fibrates, LY518674 did not change HDL apoA-I levels in response to due to an increased turnover of apoA-I where an increased fractional catabolic rate entirely counteracted the increase in apoA-I production. The changes in apoB metabolism in response to PPAR-alpha activation with fibrates and specific PPAR-alpha agonists would be expected to reduce the risk of cardiovascular disease. However, the benefit of the enhanced turnover of HDL apoA-I in response to PPAR-alpha activation remains to be determined.

01 Aug 2009·AtherosclerosisQ2 · MEDICINE

On the mechanism for PPAR agonists to enhance ABCA1 gene expression

Q2 · MEDICINE

Article

Author: Bart Staels ; Shogo Suzuki ; Masaki Ogata ; Nobukatsu Akita ; Maki Tsujita ; Mohammad Anwar Hossain ; Frank J. Gonzalez ; Shinji Yokoyama ; Genjiro Kimura ; Tatsuya Fukutomi

Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) alpha, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR delta agonist (GW501516) and a PPAR gamma agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR alpha were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR alpha promoter was activated by all of these compounds in an LXR alpha-dependent manner, and partially in a PPAR alpha-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR alpha-dependent manner in mouse fibroblast. This activation was exclusively PPAR alpha-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.

100 Deals associated with LY-518674

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12988

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Phase 2	-	Eli Lilly & Co.	06 Nov 2008
Hypercholesterolemia	Phase 2	US	Eli Lilly & Co.	06 Nov 2008
Hypertension	Phase 2	SE	Eli Lilly & Co.	01 Jun 2006
Metabolic Syndrome	Phase 2	US	Eli Lilly & Co.	01 Jan 2006
Lipid Metabolism Disorders	Phase 2	US	-	-