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.

Physicochemical Properties

Molecular Formula	C₂₁H₂₉N₅O₆S
Molecular Weight	479.55
Exact Mass	479.183
Elemental Analysis	C, 52.60; H, 6.10; N, 14.60; O, 20.02; S, 6.69
CAS #	897732-93-3
Related CAS #	897732-93-3
PubChem CID	11691484
Appearance	White to khaki solid powder
Density	1.3±0.1 g/cm3
Boiling Point	648.3±55.0 °C at 760 mmHg
Flash Point	345.9±31.5 °C
Vapour Pressure	0.0±1.9 mmHg at 25°C
Index of Refraction	1.570
LogP	2.9
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	8
Heavy Atom Count	33
Complexity	740
Defined Atom Stereocenter Count	0
SMILES	O=C(N1CCC(OC2C(OC)=C(NC3C(C)=NC(S(C)(=O)=O)=CC=3)N=CN=2)CC1)OC(C)C
InChi Key	WPDCHTSXOPUOII-UHFFFAOYSA-N
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)
Chemical Name	propan-2-yl 4-[5-methoxy-6-[(2-methyl-6-methylsulfonylpyridin-3-yl)amino]pyrimidin-4-yl]oxypiperidine-1-carboxylate
Synonyms	APD597; APD-597; APD 597; JNJ-38431055; JNJ 38431055; JNJ38431055
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	hGPR119 ( EC50 = 46 nM ); CYP2C9 ( IC50 = 5.8 μM )
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.
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.
Enzyme Assay	APD597 is a GPR119 agonist with an EC50 of 46 nM for hGPR119 that is used to treat type 2 diabetes.
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.
Animal Protocol
References	[1]. Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists. Bioorg Med Chem Lett. 2014 Sep 1;24(17):4332-4335. [2]. The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo. Sci Rep. 2017 Jun 28;7(1):4351. [3]. Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improvedprofile. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1750-1755.
Additional Infomation	JNJ-38431055 has been used in trials studying the treatment of Diabetes Mellitus, Type 2.

Solubility Data

Solubility (In Vitro)

DMSO: ≥ 19 mg/mL Water: N/A Ethanol: N/A

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

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.