PPARα; PPARδ; PPARγ
Indeglitazar (PPM 204 / PLX 204) is a pan-agonist of peroxisome proliferator-activated receptors (PPARs), activating PPARα, PPARγ, and PPARδ. (Cellular transactivation EC50s (μM): PPARα, 0.99; PPARγ, 0.85; PPARδ, 1.3. Biochemical AlphaScreen EC50s (μM): PPARα, 0.51; PPARγ, 0.37; PPARδ, 2.7) [1]

In a preadipocyte differentiation assay, which evaluates the cells' functional insulin sensitization ability, Indeglitazar exhibits an EC50 of 0.32 μM while Rosiglitazone displays an EC50 of 13 nM. Despite this, the two compounds yield comparable maximal responses[1].

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In cellular transcriptional transactivation assays, Indeglitazar acted as a full agonist against PPARα but showed significantly reduced (partial) agonist responses against PPARγ (45% ± 10% relative to the full agonist rosiglitazone) and PPARδ (67% ± 18% relative to the full agonist L-165041). [1]
In a preadipocyte differentiation assay, Indeglitazar stimulated differentiation with an EC50 of 0.32 μM, which was less potent than rosiglitazone (EC50 0.013 μM), although the maximal responses were comparable. [1]
TaqMan analysis of mature adipocytes treated with Indeglitazar showed up-regulation of the adipokine adiponectin, but the achieved levels were only half of those stimulated by the full PPARγ agonist rosiglitazone. [1]
Indeglitazar (at 10 μM) showed no activation of other tested nuclear receptors, no significant activity against major cytochrome P450 enzymes, and no significant activity against a diverse panel of other therapeutic targets. [1]

The Zucker rat model of diabetes is used to perform a preliminary evaluation of in vivo activity. Following intravenous treatment with 10 mg/kg Indeglitazar once daily for three weeks, there is a significant reduction in glucose, HbA_1C, triglycerides, and total cholesterol. The observed decreases in glucose and HbA_1C are accomplished in an adiponectin-independent manner because, remarkably, the level of Adiponectin (on day 21) is essentially unchanged in treated vs. untreated animals (4.8 mcg/mL vs. 4.9 mcg/mL). These variations in Indeglitazar's in vivo effects could be the result of interactions between the compound's three PPAR activities, its SPPARM profile, or a combination of these factors. Using the ob/ob model of diabetes and insulin resistance, the oral activity of Indeglitazar is evaluated. Triglycerides, free fatty acid, insulin, and glucose are all markedly reduced by indglitazar[1].

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In Zucker diabetic fatty rats, intravenous treatment with Indeglitazar (10 mg/kg once daily for 3 weeks) significantly lowered plasma glucose, HbA1c, triglycerides, and total cholesterol compared to vehicle-treated controls. Notably, adiponectin levels in treated animals remained essentially unchanged (4.8 mcg/ml vs 4.9 mcg/ml in controls), and body weight gain was reduced by 4.8% compared to controls. [1]
In ob/ob mice, oral administration of Indeglitazar (10 mg/kg) significantly decreased plasma glucose, insulin, triglycerides, and free fatty acid levels, with efficacy comparable to pioglitazone (10 mg/kg) on glucose, triglycerides, and FFAs, but with a greater reduction in insulin levels. Indeglitazar increased adiponectin levels only 1.9-fold compared to a 3.5-fold increase by pioglitazone. Body weight changes were not significantly different. [1]
In diet-induced obese (DIO) hamsters, oral treatment with Indeglitazar (30 mg/kg for 2 weeks) resulted in significant weight loss compared to both control and fenofibrate-treated groups. Both fed and fasted triglyceride levels were significantly reduced in the Indeglitazar group. [1]
In obese bonnet macaques, oral Indeglitazar treatment for 6 weeks induced a dose-dependent decrease in body weight. [1]
Metabolomic (Lipomics) analysis of mice treated with Indeglitazar showed significant alterations in lipid metabolite profiles (e.g., depletion of essential fatty acids in cholesterol esters and triglycerides, enrichment of saturated and monounsaturated fatty acids, increased Δ-6 desaturase activity), indicative of engagement of all three PPAR isoforms (PPARα, γ, and δ) in vivo. [1]

Before crystallization, equal volumes of a protein or compound sample are mixed with reservoir solution containing 27% polyethylene glycol (PEG) 4000, 0.1 M 2-(bis-(2-hydroxy-ethyl)-amino)-2-hydroxymethyl-propane-1,3-diol (BisTris) buffer at pH 6.5, 0.2 M ammonium acetate, and 5% glycerol. The purified PPAR_ LBD protein is diluted to 12 mg/mL, and 1 mM of Indeglitazar and a 2x molar excess of steroid receptor coactivator-1 (SRC-1) peptide are added prior to crystallization. Before being flash-frozen in liquid nitrogen for data collection, the crystals are soaked in cryo-protective buffer (30% PEG 4000, 0.1 M BisTris buffer at pH 6.5, 0.2 M ammonium acetate, and 5% glycerol)[1].

Biochemical agonist activity was determined using AlphaScreen technology. Recombinant PPAR ligand-binding domains (LBDs) were incubated with test compounds and biotinylated coactivator peptides. Compound-dependent interaction between the LBD and the coactivator peptide was measured. [1]
Transcriptional transactivation activity was measured using a luciferase reporter assay. 293T cells were co-transfected with a plasmid encoding a Gal4 DNA-binding domain fused to a PPAR LBD and a reporter plasmid containing a Gal4-responsive element upstream of a luciferase gene. After transfection, cells were treated with compounds, and luciferase activity was measured to quantify receptor activation. [1]
Preadipocyte differentiation assay: Preadipocytes were treated with compounds, and differentiation was assessed by measuring functional insulin sensitization capability (protocol details in SI). [1]
TaqMan analysis: Mature adipocytes were treated with compounds, RNA was extracted, and the expression level of adiponectin mRNA was quantified using TaqMan real-time PCR. [1]

Rats: To ZDF/GmiCrl-fa/fa rats, indentistazar is given intravenously (10% SolutolHS15, 10% ethanol, 80% saline) once a day. Blood samples are examined 21 days before and after the treatment, which is started at 7-8 weeks of age.
Mice: Ob/ob mouse experiment. Nine-week-old B6.V-Lepob mice are given either indagoglitazar (10 mg/kg) or pioglitazone (30 mg/kg) orally for a period of 14 days. Prior to dosing, compounds are suspected in 0.5% methylcellulose and 2% Tween 80. Blood is drawn on the final day to measure adiponectin, insulin, triglycerides, and free fatty acids.

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Zucker rat model: Zucker diabetic fatty rats were treated intravenously with Indeglitazar at a dose of 10 mg/kg, once daily for 3 weeks. Metabolic parameters (glucose, HbA1c, lipids, adiponectin) and body weight were monitored. [1]
ob/ob mouse model: ob/ob mice were treated orally with Indeglitazar at a dose of 10 mg/kg. Plasma glucose, insulin, triglycerides, free fatty acids, adiponectin, and body weight were measured. Pioglitazone (10 mg/kg) was used as a reference. [1]
Hamster DIO model: Hamsters fed a high-fat diet were treated orally with Indeglitazar at a dose of 30 mg/kg for 2 weeks. Body weight and triglyceride levels (fed and fasted state) were measured. Fenofibrate was used as a PPARα reference. [1]
Obese bonnet macaque model: Obese bonnet macaques were treated orally with Indeglitazar for 6 weeks. Body weight was monitored. [1]
Pharmacokinetic studies: Sprague-Dawley rats and rhesus monkeys were administered Indeglitazar orally (rats: 10 mg/kg; monkeys: 2 mg/kg) under fasted conditions to determine pharmacokinetic parameters (Cmax, AUC, t1/2, bioavailability F%). [1]

In Sprague-Dawley rats (10 mg/kg orally, fasting), the Cmax of Indeglitazar was 20,250 ng/ml, the AUC0-∞ was 59,830 nghr/ml, the terminal half-life (t1/2) was 1.4 hours, and the oral bioavailability (F) was 98%. [1] In rhesus monkeys (2 mg/kg orally, fasting), the Cmax of Indeglitazar was 12,319 ng/ml, the AUC0-∞ was 217,100 nghr/ml, the t1/2 was 23.9 hours, and the oral bioavailability was 72%. [1]
In a single-dose escalation trial in humans (2 mg and 4 mg on an empty stomach), the Cmax of Indeglitazar was 6880 and 8517 ng/ml, respectively; the AUC0-∞ was 128,700 and 141,900 nghr/ml, respectively; and the t1/2 was 17.8 and 21.3 hours, respectively. Oral bioavailability (F) was not assessed in this human study. [1]

In a preliminary clinical trial in healthy volunteers (single escalation doses of 2 mg and 4 mg), Indeglitazar was reported to be safe and well-tolerated. [1]

[1]. Scaffold-based discovery of Indeglitazar, a PPAR pan-active anti-diabetic agent. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):262-7.

The discovery of Indeglitazar employed a scaffold-based drug discovery approach that combined low-affinity biochemical screening with high-throughput co-crystallization. [1]
Its structural basis for partial agonistic effects on PPARγ (and PPARδ) lies in its ability to recruit a structural water molecule to the signaling interface between the ligand and key receptor residues (e.g., Tyr-327 in PPARγ), thereby reducing the stability of AF-2 (activator-2) helical binding and decreasing transcriptional activity. [1]
It is described as a selective PPAR modulator (SPPARM) with pan-agonist properties. Its goal is to potentially reduce the side effects associated with full PPARγ agonists (e.g., significant weight gain, edema) while providing comprehensive metabolic benefits (glycemic control, lipid reduction, weight maintenance/loss). [1]
Indeglitazar has entered a Phase II clinical trial for the treatment of type 2 diabetes mellitus (T2DM). [1]

C19H19NO6S

389.42226

389.093

C, 58.60; H, 4.92; N, 3.60; O, 24.65; S, 8.23

835619-41-5

835619-41-5

11395145

White to gray solid powder

3.993

1

6

7

27

610

0

O=C(CCC1C2C(=CC=C(C=2)OC)N(S(C2C=CC(OC)=CC=2)(=O)=O)C=1)O

YMPALHOKRBVHOJ-UHFFFAOYSA-N

InChI=1S/C19H19NO6S/c1-25-14-4-7-16(8-5-14)27(23,24)20-12-13(3-10-19(21)22)17-11-15(26-2)6-9-18(17)20/h4-9,11-12H,3,10H2,1-2H3,(H,21,22)

3-[5-methoxy-1-(4-methoxyphenyl)sulfonylindol-3-yl]propanoic acid

PLX-204; PLX204; PLX 204; PPM-204; PPM204; PPM 204

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~256.8 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.42 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)