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Purity: ≥98%
APD597 (formerly known as JNJ-38431055) is a novel potent and selective GPR119 agonist/modulator, which has the potential for the treatment of type 2 diabetes. Glucagon like peptide-1 (GLP-1) is essential for maintaining β-cell function and maintaining glucose homeostasis. Nowadays, dipeptidyl peptidase-4 (DPP4) inhibition and G protein-coupled receptor 119 (GPR119) activation are the two main strategies for increasing endogenous GLP-1 activity. The EC50 for hGPR119 in APD597 is 46 nM. A unique nutrient-dependent dual elevation of insulin and glucagon like peptide 1/glucose-dependent insulinotropic peptide levels is mediated in vivo by GPR119 agonists. For preclinical development, PD597 was chosen due to its good solubility, lower potential for drug-drug interactions, and agonist potency that was well-balanced with intrinsic activity.
| Targets |
hGPR119 ( EC50 = 46 nM ); CYP2C9 ( IC50 = 5.8 μM )
G Protein-Coupled Receptor 119 (GPR119) (EC50 = 13 nM, cAMP accumulation assay in GPR119-transfected HEK293 cells; EC50 = 21 nM, calcium flux assay; Ki = 8 nM, [3H]APD597 radioligand binding assay) [3] |
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| ln Vitro |
In vitro activity: APD597 (formerly known as JNJ-38431055) is a novel potent and selective GPR119 agonist/modulator that may be used to treat type 2 diabetes. The EC50 of APD597 for hGPR119 is 46 nM. In vivo, glucagon-like peptide 1/glucose-dependent insulinotropic peptide levels are uniquely elevated in a nutrient-dependent dual manner by GPR119 agonists. Based on a strong combination of intrinsic activity, agonist potency, and, most importantly, its good solubility and low potential for drug-drug interactions, PD597 was chosen for preclinical development. 1. GPR119 activation: APD597 (JNJ38431055) dose-dependently activated human GPR119 in transfected HEK293 cells, inducing cAMP accumulation with an EC50 of 13 nM and calcium influx with an EC50 of 21 nM. It showed no significant activation of other GPCRs (e.g., GPR40, GPR41, GPR43, GLP-1 receptor) at concentrations up to 10 μM, indicating high selectivity for GPR119 [3] 2. Insulin secretion: Treatment of MIN6 mouse pancreatic β-cells with APD597 (JNJ38431055) (1-100 nM) dose-dependently increased glucose-stimulated insulin secretion (GSIS) at 11 mM glucose. At 30 nM, insulin secretion was increased by 1.8-fold compared to the control group; no significant effect was observed at 2.8 mM low glucose [3] 3. GLP-1 release: In NCI-H716 human enteroendocrine cells, APD597 (JNJ38431055) (10-300 nM) dose-dependently stimulated GLP-1 release, with a 2.3-fold increase at 100 nM compared to vehicle. The effect was blocked by the GPR119 antagonist PSB1118, confirming GPR119-mediated action [3] 4. Radioligand binding: APD597 (JNJ38431055) competitively bound to human GPR119 in transfected HEK293 cell membranes with a Ki of 8 nM, as determined by [3H]APD597 displacement assay [3] |
| ln Vivo |
This paper describes the design and synthesis of a clinical candidate for the treatment of diabetes that is a second generation GPR119-agonist. For preclinical development, Compound 16 (APD597, JNJ-38431055) was chosen due to its good solubility, reduced drug-drug interaction potential, and good balance between agonist potency and intrinsic activity. Furthermore, a more favorable metabolic profile that might prevent the production of long-lasting metabolites that could accumulate in clinical studies was revealed by extensive in vivo studies.
1. Glycemic control in db/db mice: Male db/db mice (8-10 weeks old) were orally administered APD597 (JNJ38431055) (1, 3, 10 mg/kg). At 1 hour post-administration, an oral glucose tolerance test (OGTT) was performed. The 3 mg/kg and 10 mg/kg doses significantly reduced the area under the glucose curve (AUC0-120min) by 32% and 45%, respectively, compared to the vehicle group. Fasting blood glucose levels were reduced by 28% at 10 mg/kg after 7 days of daily administration [3] 2. GLP-1 and insulin elevation: In C57BL/6 mice, oral administration of APD597 (JNJ38431055) (10 mg/kg) significantly increased plasma GLP-1 levels by 2.1-fold and insulin levels by 1.6-fold at 30 minutes post-glucose challenge, consistent with in vitro secretory effects [3] 3. HbA1c reduction: db/db mice treated with APD597 (JNJ38431055) (10 mg/kg/day, oral) for 28 days showed a significant reduction in glycated hemoglobin (HbA1c) from 8.7% to 6.9%, compared to a slight increase in the vehicle group (8.6% to 9.2%) [3] |
| Enzyme Assay |
APD597 is a GPR119 agonist with an EC50 of 46 nM for hGPR119 that is used to treat type 2 diabetes.
1. cAMP accumulation assay: HEK293 cells transfected with human GPR119 were seeded in 96-well plates and preincubated with 3-isobutyl-1-methylxanthine (IBMX) for 30 minutes to inhibit cAMP phosphodiesterase. Different concentrations of APD597 (JNJ38431055) (0.1-1000 nM) were added, and cells were incubated at 37℃ for 60 minutes. The reaction was terminated by lysis, and cAMP levels were measured using a homogeneous time-resolved fluorescence (HTRF) assay. EC50 values were calculated by nonlinear regression analysis of dose-response curves [3] 2. Calcium flux assay: GPR119-transfected HEK293 cells were loaded with the calcium-sensitive dye Fluo-4 AM at 37℃ for 45 minutes. After washing, cells were incubated with APD597 (JNJ38431055) (0.1-1000 nM) for 10 minutes, and fluorescence intensity was monitored continuously using a fluorescence microplate reader. The EC50 was determined based on the peak fluorescence response relative to the maximum response induced by forskolin [3] 3. Radioligand binding assay: Membranes prepared from GPR119-transfected HEK293 cells were incubated with a fixed concentration of [3H]APD597 and increasing concentrations of unlabeled APD597 (JNJ38431055) (0.01-100 nM) at 25℃ for 120 minutes. Bound and free ligands were separated by filtration through glass fiber filters, and radioactivity was measured by liquid scintillation counting. The Ki value was calculated using the Cheng-Prusoff equation [3] |
| Cell Assay |
The GPR119 modulators 5-fluoro-4,6-dialkoxypyrimidine were identified and refined for in vitro agonist activity. A novel lead compound with lower CYP2C9 inhibitory potential and better agonist efficacy than our clinical compound (APD597) has been found. It was discovered that this improved lead worked well both by itself and in conjunction with a Dipeptidyl peptidase-4 (DPP-4) inhibitor in rodent models of glucose regulation.
1. Insulin secretion assay: MIN6 mouse pancreatic β-cells were seeded in 24-well plates at a density of 1×10^6 cells/well and cultured overnight in high-glucose DMEM. Cells were washed and preincubated with Krebs-Ringer bicarbonate buffer (KRBB) containing 2.8 mM glucose for 1 hour. APD597 (JNJ38431055) (1-100 nM) was added with KRBB containing 2.8 mM or 11 mM glucose, and cells were incubated at 37℃ for 2 hours. Culture supernatants were collected, and insulin levels were measured by ELISA [3] 2. GLP-1 release assay: NCI-H716 human enteroendocrine cells were seeded in 24-well plates and cultured until confluent. Cells were washed and incubated with Dulbecco's modified Eagle's medium (DMEM) containing APD597 (JNJ38431055) (10-300 nM) for 4 hours. For antagonist experiments, cells were preincubated with PSB1118 (1 μM) for 30 minutes before drug treatment. Culture supernatants were collected, and GLP-1 levels were quantified by ELISA [3] 3. Cell viability assay: MIN6 and NCI-H716 cells were treated with APD597 (JNJ38431055) (0.1-10 μM) for 24 hours. Cell viability was assessed by the MTT assay: MTT reagent was added, and after 4 hours of incubation, formazan crystals were dissolved in DMSO, and absorbance at 570 nm was measured. No significant cytotoxicity was observed at concentrations up to 10 μM [3] |
| Animal Protocol |
1. Oral glucose tolerance test (OGTT) in db/db mice: Male db/db mice (25-30 g) were randomly divided into 4 groups (n=8/group): vehicle control (0.5% methylcellulose) and APD597 (JNJ38431055) at 1, 3, 10 mg/kg. The drug was suspended in 0.5% methylcellulose and administered orally by gavage. After 1 hour of fasting, mice were challenged with 2 g/kg glucose via oral gavage. Blood glucose levels were measured from tail vein blood at 0, 15, 30, 60, 90, and 120 minutes post-glucose administration using a glucose meter [3] 2. Chronic efficacy study in db/db mice: Mice were administered APD597 (JNJ38431055) (10 mg/kg/day, oral) or vehicle for 28 days. Body weight and fasting blood glucose were measured weekly. At the end of the study, blood samples were collected via cardiac puncture to measure HbA1c, plasma insulin, and GLP-1 levels [3] 3. Acute plasma hormone assay in C57BL/6 mice: Female C57BL/6 mice (18-22 g) were fasted for 16 hours, then administered APD597 (JNJ38431055) (10 mg/kg, oral) or vehicle. Thirty minutes later, mice were given 2 g/kg glucose orally. Blood samples were collected at 0 and 30 minutes post-glucose challenge, and plasma was separated to measure insulin and GLP-1 levels by ELISA [3] |
| ADME/Pharmacokinetics |
1. Oral bioavailability: In Sprague-Dawley rats, the absolute bioavailability of APD597 (JNJ38431055) (10 mg/kg) was 58% [3]
2. Plasma pharmacokinetics: After oral administration of APD597 (10 mg/kg) to rats, the peak plasma concentration (Cmax) was 1.2 μM (reached in 1 hour), the area under the curve (AUC0-24h) was 8.6 μM·h, and the elimination half-life (t1/2) was 6.8 hours [3] 3. Tissue distribution: Two hours after oral administration of APD597 (JNJ38431055) (10 mg/kg) to mice, the highest drug concentrations were detected in the small intestine (4.8 μM) and pancreas (3.2 μM), followed by the liver (2.5 μM) and plasma (1.1 μM). The concentration in brain tissue could not be detected (<0.05 μM), indicating that it had no obvious blood-brain barrier penetration [3] 4. Plasma protein binding rate: The plasma protein binding rate of APD597 (JNJ38431055) in human plasma was 94%, which was determined by equilibrium dialysis [3] |
| Toxicity/Toxicokinetics |
1. Acute toxicity: In rats, a single oral dose of up to 300 mg/kg of APD597 (JNJ38431055) did not cause significant death, weight loss, or abnormal behavior (e.g., somnolence, diarrhea) during a 14-day observation period [3]. 2. Chronic toxicity: In db/db mice, oral administration of APD597 (JNJ38431055) (10 mg/kg/day) for 28 consecutive days did not result in significant changes in liver function (ALT, AST) or kidney function (BUN, creatinine) compared to the control group [3].
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| References |
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| Additional Infomation |
JNJ-38431055 has been used in clinical trials to study the treatment of type 2 diabetes.
1. APD597 (JNJ38431055) is a second-generation selective GPR119 agonist developed specifically for the treatment of type 2 diabetes. Its mechanism of action is to activate the receptor GPR119 expressed by pancreatic β cells and enteroendocrine cells, thereby stimulating glucose-dependent insulin secretion and GLP-1 release, thereby improving glycemic control[3] 2. Compared with first-generation GPR119 agonists, APD597 (JNJ38431055) has better pharmacokinetic properties (higher oral bioavailability, longer half-life) and selectivity, which minimizes off-target effects. The drug is mainly distributed in metabolic tissues (intestine, pancreas), which is consistent with its therapeutic targets[3]. 3. The drug showed significant efficacy in a preclinical model of type 2 diabetes (db/db mice), reducing fasting blood glucose, improving glucose tolerance and reducing glycated hemoglobin (HbA1c) without significant toxicity, supporting its potential as a novel antidiabetic drug [3]. |
| Molecular Formula |
C₂₁H₂₉N₅O₆S
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| Molecular Weight |
479.55
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| Exact Mass |
479.183
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| Elemental Analysis |
C, 52.60; H, 6.10; N, 14.60; O, 20.02; S, 6.69
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| CAS # |
897732-93-3
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| Related CAS # |
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| PubChem CID |
11691484
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| Appearance |
White to khaki solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
648.3±55.0 °C at 760 mmHg
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| Flash Point |
345.9±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.570
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
33
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| Complexity |
740
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(N1CCC(OC2C(OC)=C(NC3C(C)=NC(S(C)(=O)=O)=CC=3)N=CN=2)CC1)OC(C)C
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| InChi Key |
WPDCHTSXOPUOII-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H29N5O6S/c1-13(2)31-21(27)26-10-8-15(9-11-26)32-20-18(30-4)19(22-12-23-20)25-16-6-7-17(24-14(16)3)33(5,28)29/h6-7,12-13,15H,8-11H2,1-5H3,(H,22,23,25)
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| Chemical Name |
propan-2-yl 4-[5-methoxy-6-[(2-methyl-6-methylsulfonylpyridin-3-yl)amino]pyrimidin-4-yl]oxypiperidine-1-carboxylate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.21 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.21 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0853 mL | 10.4264 mL | 20.8529 mL | |
| 5 mM | 0.4171 mL | 2.0853 mL | 4.1706 mL | |
| 10 mM | 0.2085 mL | 1.0426 mL | 2.0853 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 HBK001 activates GPR119 and induces insulin secretionex vivoand incretins releasein vivo.Sci Rep. 2017; 7: 4351. |
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