A Randomized, Double-blind, Parallel Group Study to Evaluate the Effect of 12-week Treatment With GW590735X (20ug) or GW501516X (10mg) Relative to Placebo on Measures of Adiposity and Inflammation in Overweight and Obese Subjects

The investigational drugs administered in this study activate proteins called PPARs. Data in the scientific literature on PPARs, as well as animal data and early clinical data generated by GSK with these drugs, suggest that activation of PPARs may cause the body to increase its use of fatty acids for energy, and lead to a reduction in body fat. There are also data to suggest a role for PPARs in regulating lipid (e.g., cholesterol) levels and inflammation. These and other activities of PPARs are being further explored in this clinical study.

Start Date01 Dec 2004

Sponsor / Collaborator

GSK Plc

NCT00169559 / CompletedPhase 2

A Multi-center, Three-staged, Randomized, Parallel Group, Sequential, Double-blind, fenofibrate-and Placebo-controlled Dose-response Evaluation of the Safety, Tolerability, and Effects on Plasma HDLc and TG of Eight Weeks Treatment With 1µg to 20µg Daily Doses of GW590735 in Otherwise Healthy Subjects With Low HDLc, Mildly to Moderately Elevated TG, and Normal LDLc

An eight week comparison of the investigational drug GW590735, placebo, and the marketed drug fenofibrate intended to increase the levels of "good cholesterol" and decrease levels of "bad cholesterol" in healthy patients with low levels of good cholesterol and high levels of bad cholesterol.

Start Date01 Nov 2003

Sponsor / Collaborator

GSK Plc

100 Clinical Results associated with GW-590735

100 Translational Medicine associated with GW-590735

100 Patents (Medical) associated with GW-590735

Literatures (Medical) associated with GW-590735

01 Jul 2022·Life SciencesQ3 · MEDICINE

Restoring cellular NAD(P)H levels by PPARα and LXRα stimulation to improve mitochondrial complex I deficiency

Q3 · MEDICINE

Article

Author: de Haas, Ria ; Russel, Frans G M ; Schirris, Tom J J ; Frambach, Sanne J C M ; Smeitink, Jan A M

Mitochondrial complex I (CI), the first multiprotein enzyme complex of the oxidative phosphorylation system, plays a crucial role in cellular energy production. CI deficiency is associated with a variety of clinical phenotypes, including Leigh syndrome. At the cellular level, an increased NAD(P)H concentration is one of the hallmarks in CI-deficiency.AIMSHere, we aimed to attenuate increased NAD(P)H levels by stimulation of ATP-dependent cassette (ABC)A1 and ABCG1-mediated cellular cholesterol efflux with various PPARα and LXRα agonists.MAIN METHODSMitochondrial CI-deficient fibroblasts and chemically-induced CI-deficient HeLa cells were used to study the dose-dependent effects of various PPARα and LXRα agonists on cellular NAD(P)H levels and cholesterol efflux.KEY FINDINGSIn patient-derived mitochondrial CI-deficient fibroblasts, GW590735, astaxanthin, oleoylethanolamide, and GW3965 significantly reduced the enhanced NAD(P)H levels in CI-deficient fibroblasts. Similar effects were observed in chemically-induced CI-impaired HeLa cells, in which BMS-687453, Wy14643, GW7647, T0901317, DMHCA also demonstrated a beneficial effect. Surprisingly, no effect on ABCA1- and ABCG1-mediated cholesterol efflux in HeLa cells and fibroblasts was found after treatment with these compounds. The reduction in NAD(P)H levels by GW590735 could be partially reversed by inhibition of fatty acid synthase and β-oxidation, which suggests that its beneficial effects are possibly mediated via stimulation of fatty acid metabolism rather than cholesterol efflux.SIGNIFICANCECollectively, PPARα and LXRα stimulation resulted in attenuated cellular NAD(P)H levels in CI-impaired HeLa cells and patient-derived fibroblasts and could eventually have a therapeutic potential in CI deficiency.

01 Jul 2018·Journal of Cardiovascular Pharmacology

Comparative Evaluation of Gemcabene and Peroxisome Proliferator–Activated Receptor Ligands in Transcriptional Assays of Peroxisome Proliferator–Activated Receptors: Implication for the Treatment of Hyperlipidemia and Cardiovascular Disease

Article

Author: Srivastava, Rai Ajit K. ; Bisgaier, Charles L. ; Oniciu, Daniela C.

Abstract:Gemcabene, a late-stage clinical candidate, has shown efficacy for LDL-C, non-HDL cholesterol, apoB, triglycerides, and hsCRP reduction, all risk factors for cardiovascular disease. In rodents, gemcabene showed changes in targets, including apoC-III, apoA-I, peroxisomal enzymes, considered regulated through peroxisome proliferator–activated receptor (PPAR) gene activation, suggesting a PPAR-mediated mechanism of action for the observed hypolipidemic effects observed in rodents and humans. In the current study, the gemcabene agonist activity against PPAR subtypes of human, rat, and mouse were compared with known lipid lowering PPAR activators. Surprisingly, gemcabene showed no or little PPAR-α transactivation compared with reference agonists, which showed concentration-dependent transactivation against human PPAR-α of 2.4- to 30-fold (fenofibric acid), 17-fold (GW590735), and 2.3- to 25-fold (WY-14643). These agents also showed robust transactivation of mouse and rat PPAR-α in a concentration-dependent manner. The known PPAR-δ agonists, GW1516, L165041, and GW0742, showed potent agonist activity against human, mouse, and rat receptors (ranging from 165- to 396-fold). By contrast, gemcabene at the highest concentration tested (300 μM) showed no response in mouse and rat and a marginal response against human PPAR-δ receptors (3.2-fold). For PPAR-γ, gemcabene showed no agonist activity against all 3 species at 100 μM and marginal activity (3.6- to 5-fold) at 300 μM. By contrast, the known agonists, rosiglitazone, indomethacin, and muraglitazar showed strong activation against the mouse, rat, and human PPAR-γ receptors. No clear antagonist activity was observed with gemcabene against any PPAR subtypes for all 3 species over a wide range of concentrations. In summary, the transactivation studies rule out gemcabene as a direct agonist or antagonist of PPAR-α, PPAR-γ, and PPAR-δ receptors of these 3 species. These data suggest that the peroxisomal effects observed in rodents and the lipid regulating effects observed in rodents and humans are not related to a direct activation of PPAR receptors by gemcabene.

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

Selective CETP Inhibition and PPARα Agonism Increase HDL Cholesterol and Reduce LDL Cholesterol in Human ApoB100/Human CETP Transgenic Mice

Q4 · MEDICINE

Article

Author: Issandou, Marc ; McVey, Matthew J. ; Brusq, Jean-Marie ; White, Ray F. ; Legos, Jeffrey J. ; Grillot, Didier A. ; Barone, Frank C. ; Hansen, Michael K.

Cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) cholesterol metabolism, but normal mice are deficient in CETP. In this study, transgenic mice expressing both human apolipoprotein B 100 (ApoB-100) and human CETP (hApoB100/hCETP) were used to characterize the effects of CETP inhibition and peroxisome proliferator—activated receptor α (PPARα) agonism on lipid profiles. Torcetrapib (3, 10, and 30 mg/kg), a CETP inhibitor, fenofibrate (30 mg/kg), a weak PPARα agonist, and GW590735 (3 and 10 mg/kg), a potent and selective PPARα agonist were given orally for 14 days to hApoB100/hCETP mice and lipid profiles were assessed. The average percentages of HDL, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) cholesterol fractions in hApoB100/hCETP mice were 34.8%, 61.6%, and 3.6%, respectively, which is similar to those of normolipidemic humans. Both torcetrapib and fenofibrate significantly increased HDL cholesterol and reduced LDL cholesterol, and there was a tendency for torcetrapib to reduce VLDL cholesterol and triglycerides. GW590735 significantly increased HDL cholesterol, decreased LDL and VLDL cholesterol, and significantly reduced triglycerides. Maximal increases in HDL cholesterol were 37%, 53%, and 84% with fenofibrate, torcetrapib, and GW590735, respectively. These results, in mice that exhibit a more human-like lipid profile, demonstrate an improved lipid profile with torcetrapib, fenofibrate, and GW590735, and support the use of selective PPARα agonism for the treatment of lipid disorders. In addition, these data demonstrate the use of hApoB100/hCETP transgenic mice to identify, characterize, and screen compounds that increase HDL cholesterol.

100 Deals associated with GW-590735

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Phase 2	-	Ligand Pharmaceuticals, Inc.	-
Atherosclerosis	Phase 2	US	-	-
Atherosclerosis	Phase 2	-	GSK Plc	-
Dyslipidemias	Phase 2	-	Ligand Pharmaceuticals, Inc.	-
Dyslipidemias	Phase 2	-	Ligand Pharmaceuticals, Inc.	-

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