2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]phenyl}acetic acid hydrochloride

• ChemBase ID: 73112
• Molecular Formular: C33H32Cl2F3NO3
• Molecular Mass: 618.5132896
• Monoisotopic Mass: 617.17113391
• SMILES: c1c(cc(cc1)OCCCN(Cc1cccc(c1Cl)C(F)(F)F)CC(c1ccccc1)c1ccccc1)CC(=O)O.Cl
• Canonical SMILES: OC(=O)Cc1cccc(c1)OCCCN(CC(c1ccccc1)c1ccccc1)Cc1cccc(c1Cl)C(F)(F)F.Cl
• InChI: InChI=1S/C33H31ClF3NO3.ClH/c34-32-27(15-8-17-30(32)33(35,36)37)22-38(18-9-19-41-28-16-7-10-24(20-28)21-31(39)40)23-29(25-11-3-1-4-12-25)26-13-5-2-6-14-26;/h1-8,10-17,20,29H,9,18-19,21-23H2,(H,39,40);1H
• InChIKey: NMPUWJFHNOUNQU-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 2-{3-[3-({[2-chloro-3-(trifluoromethyl)phenyl]methyl}(2,2-diphenylethyl)amino)propoxy]phenyl}acetic acid hydrochloride
• IUPAC Traditional name: C33H31ClF3NO3 hydrochloride
• Synonyms: GW-3965; GW3965 hydrochloride; 3-[3-[N-(2-Chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic acid hydrochloride; GW3965 hydrochloride

Database IDs

• CAS Number: 405911-17-3
• MDL Number: MFCD08276920
• PubChem SID: 24724494; 162038032
• PubChem CID: 16078973

CALCULATED PROPERTIES

• Acid pKa: 3.8771806
• H Acceptors: 4
• H Donor: 1
• LogD (pH = 5.5): 5.514715
• LogD (pH = 7.4): 5.5023885
• Log P: 5.519908
• Molar Refractivity: 156.0386 cm^3
• Polarizability: 59.284794 Å^3
• Polar Surface Area: 49.77 Å^2
• Rotatable Bonds: 14
• Lipinski's Rule of Five: false

PROPERTIES

Physical Property

• Solubility: DMSO: ≥20 mg/mL
• Apperance: white powder

Safety Information

• Storage Condition: -20°C
• European Hazard Symbols: Harmful (Xn)
• German water hazard class: 3
• Risk Statements: 22-41
• Safety Statements: 26-39
• GHS Pictograms: GHS05; GHS07
• GHS Signal Word: Danger
• GHS Hazard statements: H302-H318-H413
• GHS Precautionary statements: P280-P305 + P351 + P338
• Personal Protective Equipment: dust mask type N95 (US), Eyeshields, Gloves

Pharmacology Properties

• Target: liver X receptor (LXR)

Product Information

• Purity: ≥98% (HPLC)
• Salt Data: HCL
• Empirical Formula (Hill Notation): C33H31F3ClNO3 · HCl

DETAILS

Selleck Chemicals - S2630

Research Area

• Description: Cardiovascular Disease

Biological Activity

• Description: GW3965 is a potent, selective LXR agonist, which exhibits its potency in the LXRα/SRC1?LiSA and LXRα-GAL4 with EC50 of 125 nM and 190 nM, respectively.
• Targets: LXRα/SRC1?LiSA; LXRα-GAL4; LXRβ
• IC50: 125 nM ^[1]; 190 nM ^[1]; 30 nM ^[1]
• In Vitro: GW3965 recruits the steroid receptor coactivator 1 to human LXRα with EC50 of 125 nM in a cell-free ligand-sensing assay. ^[1] GW3965 shows a potent antagonistic activity against hLXRα and hLXRβ in cell-based assays with EC50 of 190 nM and 30 nM, respectively. Besides, GW3965 also sows excellent selectivity over other nuclear receptors. ^[1] In human islets, GW3965 (1 μM) reduces expression of selected pro-inflammatory cytokines including IL-8, monocyte chemotactic protein-1 and tissue factor. ^[4]
• In Vivo: In mice, GW3965 at a dose of 10 mg/kg upregulates ABCA1 expression 8-fold and raises circulating levels of HDL by 30% with C_max of 12.7 μg/mL and t_1/2 of 2 hours. ^[1] GW3965 (10mg/kg) induces expression of ABCA1 and ABCG1 and shows potent antiatherogenic activity in both LDLR?/? and apoE?/? mice. ^[2] In male sprague–dawley rats, GW3965 reduces Ang II-mediated increases in blood pressure and decreases vascular Ang II receptor gene expression. ^[3] In Glioblastoma mouse model, GW3965 results in inducible degrader of LDLR-mediated LDLR degradation, increased expression of the ABCA1 cholesterol efflux transporter, and thus potently promotes tumor cell death. ^[5]

Protocol

• Protocol: Animal Study ^[1]
• Animal Models: C57BL/6 mice
• Formulation: GW3965 is dissolved in 0.5% Methyl Cellulose.
• Doses: ≤10 mg/kg
• Administration: Administered via p.o.

References

• References: [1] Collins JL, et al. J Med Chem. 2002, 45(10), 1963-1966.
• References: [2] Joseph SB, et al. Proc Natl Acad Sci U S A. 2002, 99(11), 7604-7609.
• References: [3] Leik CE, et al. Br J Pharmacol. 2007, 151(4), 450-456.
• References: [4] Scholz H, et al. Diabetologia. 2009, 52(7), 1352-1362.
• References: [5] Guo D, et al. Cancer Discov. 2011, 1(5), 442-456.

Sigma Aldrich - G6295

Biochem/physiol Actions
GW3965 is a liver X receptor full agonist on hLXRα and hLXRβ. GW3965 has an EC50 = 125 nM in a cell-free ligand-sensing assay of LXRα and profiles as a full agonist on hLXRα and hLXRβ in cell-based assays with EC50 = 190 nM and 30 nM, respectively. It is orally active in mice. When screened against a panel of nuclear receptors, it cross-reacted with only the pregnane X receptor (PXR). The literature agonist, T0901317 (Tularik), had an EC50 = 60 nM and 85 nM in the cell-free and cell-based assays, respectively.

REFERENCES

• Collins JL, et al. J Med Chem. 2002, 45(10), 1963-1966.
• Joseph SB, et al. Proc Natl Acad Sci U S A. 2002, 99(11), 7604-7609.
• Leik CE, et al. Br J Pharmacol. 2007, 151(4), 450-456.
• Scholz H, et al. Diabetologia. 2009, 52(7), 1352-1362.
• Guo D, et al. Cancer Discov. 2011, 1(5), 442-456.