Delving into the Latest Updates on Edaglitazone with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Edaglitazone sodium (USAN), edaglitazone sodium

+ [7]

Target

PPARγ

Mechanism

PPARγ agonists(Peroxisome proliferator-activated receptor γ agonists)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2

Originator Organization

F. Hoffmann-La Roche Ltd.

Active Organization-

Inactive Organization

Hoffmann-La Roche, Inc.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC24H20N2O4S2

InChIKeyHAAXAFNSRADSMK-UHFFFAOYSA-N

CAS Registry213411-83-7

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor with an important role in lipid metabolism, inflammation and cardiovascular diseases. PPARγ ligands have inhibitory effects on platelet aggregation via the cAMP pathway, which may confer them a protective cardioprotective role. Edaglitazone and Ciglitazone are two chemically-similar thiazolidinedione (TZD) drugs that have been described as potent PPARγ agonists; however, Edaglitazone is over 100 times more potent than Ciglitazone. Here, we report a computational study to describe the ligand binding and the experimental antiplatelet profiles of Edaglitazone and Ciglitazone. Both ligands presented similar orientations within the PPARγ binding site. Their polar heads exhibit complex hydrogen bond networks with the residues at arm I pocket, while their hydrophobic tails are oriented inside arm II or the entrance pocket. The bulkier and longer tail of Edaglitazone exhibited additional hydrophobic interactions, explaining its stronger binding to PPARγ supported by binding affinity calculations. On the other hand, both Edaglitazone and Ciglitazone displayed an antiplatelet activity, but only Edaglitazone retained such effect at low concentrations. Furthermore, we evidenced that Edaglitazone increases intraplatelet cAMP levels and prevents PPARγ secretion, explaining its greater antiplatelet activity. Altogether, the more potent PPARγ agonist Edaglitazone seems to be a potent antiplatelet agent.

01 Oct 2010·European Journal of Clinical PharmacologyQ3 · MEDICINE

Influence of CYP2C19 genotype on the pharmacokinetics of R483, a CYP2C19 substrate, in healthy subjects and type 2 diabetes patients

Q3 · MEDICINE

Article

Author: Brian Tomlinson ; Siew Pheng Chan ; Mariabeth Silkey ; Cornelia Weber ; Katrijn Bogman

OBJECTIVESR483 is a thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist with anti-diabetic properties and also a cytochrome P450 2C19 (CYP2C19) substrate. The aim of the clinical studies reported here was to investigate the influence of the CYP2C19 genotype on the pharmacokinetics (PK) of R483 in healthy subjects and in type 2 diabetes mellitus (T2DM) patients.METHODSdata came from two clinical studies, one including 58 Japanese and Caucasian healthy subjects and another including 93 Asian T2DM patients. All subjects received multiple doses of R483, 20 mg once daily for the healthy subjects and 12 mg once daily for the T2DM patients. Blood samples were taken up to 24 h after the last dose to determine plasma concentrations of R483 and its major metabolites.RESULTSpoor metabolizers (PMs; CYP2C19*2/*2 or *2/*3 or *3/*3) had a higher plasma exposure and a lower clearance of the parent drug than extensive metabolizers (EMs; CYP2C19*1/*1 or *1/*2 or *1/*3). The homozygous PM/EM ratio for the area under the plasma concentration-time curve (AUC(0-24)) [95% confidence interval] was 3.9 [2.7-5.7] for healthy subjects versus 2.0 [1.5-2.6] in T2DM patients. The heterozygous EMs were all T2DM patients, the PM/EM ratio for AUC(0-24) was 1.5 [1.2-1.8]. The dose-normalized exposure to R483 was 1.2- (for PMs) and 2.4-fold (for EMs) higher in T2DM patients than in healthy subjects. R483 was well tolerated in both studies.CONCLUSIONSthe plasma exposure to R483 was significantly higher in PMs than in EMs. R483 exhibits different PK in healthy subjects and T2DM patients, and the difference in exposure between EM and PM was less pronounced in T2DM patients than in healthy subjects. Factors such as diabetes condition and age may influence the metabolism of R483. This knowledge allowed for a realistic dose recommendation for poor metabolizer T2DM patients.

01 Jul 2004·Cancer LettersQ1 · MEDICINE

Limited tumor growth (HT29) in vivo under RO205-2349 is due to increased apoptosis and reduced cell volume but not to decreased proliferation rate

Q1 · MEDICINE

Article

Author: Marcus Katoh ; Tobias Schnitzer ; Susanne Feldhaus ; Sabine Bauer ; Udo Schumacher

The peroxisome proliferator-activated receptor (PPARgamma) is a nuclear receptor that plays a regulatory role in cell differentiation and proliferation. PPARgamma was first detected in adipocytes, however, it has been shown that this receptor is also expressed in normal as well as tumor cells including malignant colonic epithelial cells. In this study, the effect of the PPARgamma agonist RO205-2349, a recently developed thiazolidinedione, on tumor growth was evaluated. For this purpose, human colon cancer cells (HT29) were grown in severe combined immunodeficient mice. Under daily RO205-2349 treatment (50 mg/kg/day) a significantly reduced tumor weight became evident after 3 weeks. In the control (n = 10) and treatment (n = 10) groups the mean tumor weights were 0.45 and 0.16 g, respectively. The mean percentages of apoptotic cells were 0.8 and 2.7% in the control and treatment groups, respectively, and the cell diameter measured on average 11.4 and 9.4 microm. In contrast, cell proliferation and differentiation, which are considered to be influenced by the PPARgamma, remained unaffected as could be seen by Ki-67 and carcinoembryonic antigen immunoreactivity indicating that increased rate of apoptosis and cell shrinkage are responsible for the differences in tumor growth. Hence, in this human/mouse xenograft model, mechanisms other than the classical activation of PPARgamma are likely reasons causing limited tumor growth.

100 Deals associated with Edaglitazone

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External Link

KEGG	Wiki	ATC	Drug Bank
D03941	-	-	DB06519

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 2	CA	Hoffmann-La Roche, Inc.	01 Dec 2001
Diabetes Mellitus, Type 2	Phase 2	LV	Hoffmann-La Roche, Inc.	01 Dec 2001
Diabetes Mellitus, Type 2	Phase 2	RO	Hoffmann-La Roche, Inc.	01 Dec 2001
Diabetes Mellitus, Type 2	Phase 2	PA	Hoffmann-La Roche, Inc.	01 Dec 2001
Diabetes Mellitus, Type 2	Phase 2	LT	Hoffmann-La Roche, Inc.	01 Dec 2001
Diabetes Mellitus, Type 2	Phase 2	EE	Hoffmann-La Roche, Inc.	01 Dec 2001
Diabetes Mellitus, Type 2	Phase 2	BG	Hoffmann-La Roche, Inc.	01 Dec 2001
Diabetes Mellitus, Type 2	Phase 2	GB	Hoffmann-La Roche, Inc.	01 Dec 2001
Diabetes Mellitus, Type 2	Phase 2	US	Hoffmann-La Roche, Inc.	01 Dec 2001
Diabetes Mellitus, Type 2	Phase 2	PR	Hoffmann-La Roche, Inc.	01 Dec 2001