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) plays a vital role in glucose homeostasis and sustaining β-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). APD597 has EC50 of 46 nM for hGPR119. GPR119 agonists mediate a unique nutrient-dependent dual elevation of both insulin and glucagon like peptide 1/glucose-dependent insulinotropic peptide levels in vivo. PD597 was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential.
理化性质和储存条件
| Molecular Weight (MW) | 479.55 |
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| Formula | C21H29N5O6S |
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| CAS No. | 897732-93-3 |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: ≥ 19 mg/mL |
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| Water: N/A |
| Ethanol: N/A |
| Solubility (In vivo) | CC1=NC(S(C)(=O)=O)=CC=C1NC2=NC=NC(OC3CCN(C(OC(C)C)=O)CC3)=C2OC |
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| Synonyms | APD597; APD-597; APD 597; JNJ-38431055; JNJ 38431055; JNJ38431055 |
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实验参考方法
| In Vitro | In vitro activity: 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. APD597 has EC50 of 46 nM for hGPR119. GPR119 agonists mediate a unique nutrient-dependent dual elevation of both insulin and glucagon like peptide 1/glucose-dependent insulinotropic peptide levels in vivo. PD597 was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential.
Kinase Assay: APD597 is a GPR119 agonist intended for the treatment of type 2 diabetes, with EC50 of 46 nM for hGPR119.
Cell Assay: A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor. |
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| In Vivo | The design and synthesis of a second generation GPR119-agonist clinical candidate for the treatment of diabetes is described. Compound 16 (APD597, JNJ-38431055) was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long lasting metabolites with the potential to accumulate in clinical studies. |
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| References | Bioorg Med Chem Lett. 2014 Sep 1;24(17):4332-5; Bioorg Med Chem Lett. 2012 Feb 15;22(4):1750-5. |
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