(1R,2S)-2-cyclohexyl-1-[4-(cyclopropanesulfonyl)phenyl]-N-(5-{[2-(pyrrolidin-1-yl)ethyl]sulfanyl}-1,3-thiazol-2-yl)cyclopropane-1-carboxamide

• ChemBase ID: 73130
• Molecular Formular: C28H37N3O3S3
• Molecular Mass: 559.80668
• Monoisotopic Mass: 559.19970506
• SMILES: c1c(ccc(c1)[C@]1(C[C@H]1C1CCCCC1)C(=O)Nc1ncc(s1)SCCN1CCCC1)S(=O)(=O)C1CC1
• Canonical SMILES: O=C([C@@]1(C[C@H]1C1CCCCC1)c1ccc(cc1)S(=O)(=O)C1CC1)Nc1ncc(s1)SCCN1CCCC1
• InChI: InChI=1S/C28H37N3O3S3/c32-26(30-27-29-19-25(36-27)35-17-16-31-14-4-5-15-31)28(18-24(28)20-6-2-1-3-7-20)21-8-10-22(11-9-21)37(33,34)23-12-13-23/h8-11,19-20,23-24H,1-7,12-18H2,(H,29,30,32)/t24-,28-/m0/s1
• InChIKey: QIIVJLHCZUTGSD-CUBQBAPOSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (1R,2S)-2-cyclohexyl-1-[4-(cyclopropanesulfonyl)phenyl]-N-(5-{[2-(pyrrolidin-1-yl)ethyl]sulfanyl}-1,3-thiazol-2-yl)cyclopropane-1-carboxamide
• IUPAC Traditional name: (1R,2S)-2-cyclohexyl-1-[4-(cyclopropanesulfonyl)phenyl]-N-(5-{[2-(pyrrolidin-1-yl)ethyl]sulfanyl}-1,3-thiazol-2-yl)cyclopropane-1-carboxamide
• Synonyms: LY2608204

Database IDs

• CAS Number: 1234703-40-2
• PubChem SID: 162038050
• PubChem CID: 46832368

CALCULATED PROPERTIES

• Acid pKa: 10.667359
• H Acceptors: 5
• H Donor: 1
• LogD (pH = 5.5): 3.0209467
• LogD (pH = 7.4): 4.784099
• Log P: 5.4814215
• Molar Refractivity: 152.0278 cm^3
• Polarizability: 59.71701 Å^3
• Polar Surface Area: 79.37 Å^2
• Rotatable Bonds: 10
• Lipinski's Rule of Five: false

PROPERTIES

Safety Information

• Storage Condition: -20°C

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S2155

Research Area

• Description: Metabolic Disease

Biological Activity

• Description: LY2608204 activates glucokinase (GK) with EC50 of 42 nM.
• Targets: GK
• IC50: 42 nM (EC50) ^[1]
• In Vitro: LY2608204 activates glucokinase (GK) with EC50 of 42 nM at 10 mM glucose with a concentration dependent manner at lower glucose concentrations. LY2608204 also stimulates glucose metabolism in rat insulinoma INS1-E cells with EC50 of 579 nM. ^[1]
• In Vivo: LY2608204 decreases plasma glucose in a dose-dependent manner at both fasted and postprandial glucose levels. A maximal lowering of glucose AUC versus the untreated control group is observed with the high dose (30 mg/kg) and represents a 42% decrease. Interpolation of the data show that a 20% glucose AUC decrease occurs at an average LY2608204 concentration of 99 ng/mL (179 nM) in plasma, corresponding to a 6.9 mg/kg LY2608204 dose. The in vivo blood brain barrier permeability of LY2608204 results in a mean brain/plasma ratio of 0.17 five minutes post-dose with a mean total brain level of 0.539 nmol/g. ^[1]

Protocol

• Protocol: Kinase Assay ^[1]
• Glucokinase assay: The human islet GK isoform is expressed in E. coli as (His)₆-tagged fusion protein and purified with metal chelate affinity chromatography. After purification the enzyme is stored in aliquots at concentration 0.8 mg/mL in 25 mM sodium phosphate, 150 mM sodium chloride, 100 mM imidazole, 1 mM dithiothreitol, 50% glycerol at ?80 °C. The assay is performed in flat bottom 96-well plates in a final incubation volume of 100 μL. The incubation mixture consists of 25 mM HEPES (pH7.4), 50 mM potassiumchloride, 2.5 mM magnesiumchloride, 2 mM dithiothreitol, 4 U/mL glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides, 5 mM ATP, 1 mM NAD and a set concentration of glucose. LY2608204 is dissolved in DMSO and then added to the reaction mixture giving the final DMSO concentration of 10%. The reaction is initiated by addition of 20 μL GK and runs for 20 min at 37 °C. The amount of formed NADH is measured as an increase in absorbance at 340 nm using a microplate reader. Absorbance values are used for EC50 calculations.
• Protocol: Animal Study ^[1]
• Animal Models: Male Wistar rats at a weight of 225-250 g
• Formulation: LY2608204 is suspended in a 1:1 mixture of solutol/ethanol in a bath sonicator (10% of total volume). The obtained suspension is then diluted with 9 volumes of 10% aqueous solutol solution.
• Doses: 1, 3, 6, 10, 20 and 30 mg/kg
• Administration: Orally, rats are given a 2 g/kg oral glucose bolus 2 hours after LY2608204 administration.

References

• References: [1] US Patent, 8063079, 2011.

REFERENCES

• US Patent, 8063079, 2011.