2-ethoxy-4-({[(1S)-3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl]carbamoyl}methyl)benzoic acid

• ChemBase ID: 788
• Molecular Formular: C27H36N2O4
• Molecular Mass: 452.58574
• Monoisotopic Mass: 452.26750764
• SMILES: O=C(N[C@H](c1c(N2CCCCC2)cccc1)CC(C)C)Cc1cc(OCC)c(cc1)C(=O)O
• Canonical SMILES: CCOc1cc(ccc1C(=O)O)CC(=O)N[C@H](c1ccccc1N1CCCCC1)CC(C)C
• InChI: InChI=1S/C27H36N2O4/c1-4-33-25-17-20(12-13-22(25)27(31)32)18-26(30)28-23(16-19(2)3)21-10-6-7-11-24(21)29-14-8-5-9-15-29/h6-7,10-13,17,19,23H,4-5,8-9,14-16,18H2,1-3H3,(H,28,30)(H,31,32)/t23-/m0/s1
• InChIKey: FAEKWTJYAYMJKF-QHCPKHFHSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 2-ethoxy-4-({[(1S)-3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl]carbamoyl}methyl)benzoic acid
• IUPAC Traditional name: 2-ethoxy-4-({[(1S)-3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl]carbamoyl}methyl)benzoic acid; repaglinide
• Brand Name: Prandin; GlucoNorm
• Synonyms: (S)-(+)-2-Ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoic acid; Repaglinide; (S)-2-Ethoxy-4-[2-[[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoic Acid; AG-EE-623; Repaglinida [INN-Spanish]; Repaglinidum [INN-Latin]; AG-EE 388 ZW; AG-EE 623 ZW; repaglinide; Repaglinide; Prandin; GlucoNorm; NovoNorm

Database IDs

• CAS Number: 135062-02-1
• MDL Number: MFCD00906179
• PubChem SID: 46508150; 160964251; 24724596
• PubChem CID: 65981

CALCULATED PROPERTIES

JChem

• Molar Refractivity: 131.8281 cm^3
• Polarizability: 50.317257 Å^3
• Polar Surface Area: 78.87 Å^2
• Rotatable Bonds: 10
• Lipinski's Rule of Five: true
• Acid pKa: 3.6754997
• H Acceptors: 5
• H Donor: 2
• LogD (pH = 5.5): 3.3981318
• LogD (pH = 7.4): 1.9463284
• Log P: 3.9468045

ALOGPS 2.1

• Solubility (Water): 2.94e-03 g/l
• Log P: 5.05
• LOG S: -5.19

PROPERTIES

Physical Property

• Solubility: Chloroform; DMSO: >20 mg/mL; Methanol
• Apperance: white solid; White Solid
• Melting Point: 129-130.2 °C; 133-135°C
• Hydrophobicity(logP): 5.9

Safety Information

• Storage Condition: -20°C; -20°C Freezer
• RTECS: DI0876305
• German water hazard class: 2
• Personal Protective Equipment: Eyeshields, Gloves, type N95 (US), type P1 (EN143) respirator filter
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: potassium channel
• Gene Information: human ... KCNJ1(3758)
• Mechanism of Action: Stimulating the release of insulin from the pancreas by closing ATP-dependent potassium channels in the membrane of the beta cells

Product Information

• Purity: ≥98% (HPLC)
• Salt Data: Free Base
• Application(s): Antihyperglycaemic agent used in the treatment of type II diabetes
• Empirical Formula (Hill Notation): C27H36N2O4

DETAILS

DrugBank - DB00912

• Drug Groups: approved; investigational
• Description: Repaglinide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It belongs to the meglitinide class of short-acting insulin secretagogues, which act by binding to β cells of the pancreas to stimulate insulin release. Repaglinide induces an early insulin response to meals decreasing postprandial blood glucose levels. It should only be taken with meals and meal-time doses should be skipped with any skipped meal. Approximately one month of therapy is required before a decrease in fasting blood glucose is seen. Meglitnides may have a neutral effect on weight or cause a slight increase in weight. The average weight gain caused by meglitinides appears to be lower than that caused by sulfonylureas and insulin and appears to occur only in those na?ve to oral antidiabetic agents. Due to their mechanism of action, meglitinides may cause hypoglycemia although the risk is thought to be lower than that of sulfonylureas since their action is dependent on the presence of glucose. In addition to reducing postprandial and fasting blood glucose, meglitnides have been shown to decrease glycosylated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Meglitinides appear to be more effective at lowering postprandial blood glucose than metformin, sulfonylureas and thiazolidinediones. Repaglinide is extensively metabolized in the liver and excreted in bile. Repaglinide metabolites do not possess appreciable hypoglycemic activity. Approximately 90% of a single orally administered dose is eliminated in feces and 8% in urine.
• Indication: For the treatment of non-insulin dependent-diabetes mellitus in conjunction with diet and exercise.
• Pharmacology: Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Repaglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-dependent manner.
• Toxicity: LD₅₀ >1 g/kg (rat) (W. Grell)
• Affected Organisms: Humans and other mammals
• Biotransformation: Repaglinide is rapidly metabolized via oxidation and dealkylation by cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2). Further oxidation produces the aromatic amine derivative (M1). Glucuronidation of the carboxylic acid group of repaglinide yields an acyl glucuronide (M7). Several other unidentified metabolites have been detected. Repaglinide metabolites to not possess appreciable hypoglycemic activity.
• Absorption: Rapidly and completely absorbed following oral administration. Peak plasma concentrations are observed within 1 hour (range 0.5-1.4 hours). Absolutely bioavailability is approximately 56%. Maximal biological effect is observed within 3-3.5 hours and plasma insulin levels remain elevated for 4-6 hours
• Half Life: 1 hour
• Protein Binding: >98% (e.g. to to albumin and α1-acid glycoprotein)
• Elimination: 90% eliminated in feces (<2% as unchanged drug), 8% in urine (0.1% as unchanged drug)
• Distribution: 31 L following IV administration in healthy individuals
• Clearance: 33-38 L/hour following IV administration
• External Links: Wikipedia; RxList; PDRhealth; Drugs.com

Selleck Chemicals - S1426

Research Area: Endocrinology
Biological Activity:
Repaglinide is for the treatment of type II diabetes. Repaglinide belongs to the meglitinide class of blood glucose-lowering drugs. Repaglinide lowers blood glucose by stimulating the release of insulin from the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. [1]

Sigma Aldrich - R9028

Biochem/physiol Actions
Repaglinide is a potent short-acting insulin secretagogue that acts by closing ATP-sensitive potassium (KATP) channels in the plasma membrane of the pancreatic beta cell. It represents a new class of insulin secretagogues, structurally unrelated to sulphonylureas, which were developed for the treatment of type 2 diabetes.

Toronto Research Chemicals - R144500

Non-sulfonylurea oral hypoglycemic agent. Used as an antidiabetic.

REFERENCES

• http://en.wikipedia.org/wiki/Repaglinide
• Wolffenbuttel, B.H.R., et al.: Eur. J. Clin. Pharmacol., 45, 113 (1993)
• Ampudia-Blasco, F.J., et al.: Diabetologia, 37, 703 (1993)
• Ger. Pat., 1987, Thomae, 3 522 604; CA, 106, 196260j, (synth)
• Eur. Pat., 1989, 147 850; CA, 104, 5651p
• Verspohl, E.J. et al., J. Pharm. Pharmacol., 1990, 42, 230, (pharmacol)
• Wolffenbuttel, B.H.R. et al., Eur. J. Clin. Pharmacol., 1993, 45, 113, (use)
• Pat. Coop. Treaty (WIPO), 1993, Thomae, 93 00 337; CA, 118, 254759q, (synth, isomers)