Omarigliptin (formerly known as MK-3102; MK3102) is a potent, selective, oral and long-acting inhibitor of DPP-4 (dipeptidyl peptidase 4) with antidiabetic effects. It inhibits DPP-4 with an IC50 of 1.6 nM. Omarigliptin is highly selective over all proteases tested (IC50 > 67 μM). It has weak ion channel activity (IC50 > 30 μmol/L at IKr, Caγ1.2, and Naγ1.5). Additionally, an IC50 > 10 μmol/L was obtained in all assays in an expansive selectivity counterscreen (168 radioligand binding or enzymatic assays). Omarigliptin binds rapidly and competitively to the active site of DPP-4, a process that is reversible and highly selective, and thus leads to increased levels of insulin and decreased levels of glucagon under hyperglycaemic conditions. It has excellent pharmacokinetic profiles suitable for once-weekly dosing and is currently in phase 3 clinical trial.
理化性质和储存条件
| Molecular Weight (MW) | 398.43 |
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| Formula | C17H20F2N4O3S |
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| CAS No. | 1226781-44-7 |
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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: 79 mg/mL (198.27 mM) |
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| Water: <1 mg/mL |
| Ethanol: <1 mg/mL |
| SMILES | N[C@@H]1[C@@H](C2=CC(F)=CC=C2F)OC[C@H](N3CC4=NN(S(=O)(C)=O)C=C4C3)C1 |
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| Synonyms | MK-3102; MK3102; MK 3102 |
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实验参考方法
| In Vitro | In vitro activity: Omarigliptin (formerly known as MK-3102) is a potent, selective and long-acting inhibitor of DPP-4 ( dipeptidyl peptidase 4) with IC50 of 1.6 nM. It is highly selective over all proteases tested (IC50> 67 μM). It has weak ion channel activity (IC50> 30 μmol/L at IKr, Caγ1.2, and Naγ1.5). Additionally, an IC50> 10 μmol/L was obtained in all assays in an expansive selectivity counterscreen (168 radioligand binding or enzymatic assays). Omarigliptin binds rapidly and competitively to the active site of DPP-4, a process that is reversible and highly selective, and thus leads to increased levels of insulin and decreased levels of glucagon under hyperglycaemic conditions. It has excellent pharmacokinetic profiles suitable for once-weekly dosing and is currently in phase 3 clinical trial.
Kinase Assay: Omarigliptin is a potent inhibitor of DPP-4 and is highly selective over other proteases tested (IC50> 67 μmol/L) and has weak ion channel activity (IC50> 30 μmol/L at IKr, Caγ1.2, and Naγ1.5). Additionally, an IC50> 10 μmol/L was obtained in all assays in an expansive selectivity counterscreen (168 radioligand binding or enzymatic assays). Omarigliptin binds rapidly and competitively to the active site of DPP-4, a process that is reversible and highly selective, and thus leads to increased levels of insulin and decreased levels of glucagon under hyperglycaemic conditions.
Cell Assay: |
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| In Vivo | In lean mice, when orally administered 1 h prior to dextrose challenge in an oral glucose tolerance test (OGTT), it significantly reduced blood glucose excursion in a dose-dependent manner from 0.01 mg/kg (7% reduction in glucose AUC) to 0.3 mg/kg (51% reduction). the administration of omarigliptin dose-dependently increases plasma concentrations of active GLP-1. The pharmacokinetics of omarigliptin in male Sprague–Dawley rat and beagle dog are characterized by a low plasma clearance (0.9–1.1 mL/min/kg), a volume of distribution at steady state of 0.8–1.3 L/kg, and a long terminal half-life (~11–22 h). The oral bioavailability of omarigliptin is good in both dogs and rats (~100%). Omarigliptin is well-tolerated over the duration of the study, with no mortality or physical signs noted. |
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| Animal model | Mice |
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| Formulation & Dosage | 0.01, 0.3 mg/kg; oral |
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| References | Drugs. 2015 Nov;75(16):1947-52; J Med Chem. 2014 Apr 24;57(8):3205-12. |
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