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Ruboxistaurin (LY333531)

Alias: LY-333531 LY333531 LY 333531
Cat No.:V8973 Purity: ≥98%
Ruboxistaurin (LY-333531; LY333531)is a novel, potent and specific inhibitor of PKCβ (protein kinase C) with potential antidiabetic activity.
Ruboxistaurin (LY333531)
Ruboxistaurin (LY333531) Chemical Structure CAS No.: 169939-94-0
Product category: PKC
This product is for research use only, not for human use. We do not sell to patients.
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25mg
50mg
100mg
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Other Forms of Ruboxistaurin (LY333531):

  • Ruboxistaurin (LY333531) mesylate
  • Ruboxistaurin hydrochloride (LY333531)
Official Supplier of:
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Top Publications Citing lnvivochem Products
Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Ruboxistaurin (LY-333531; LY333531) is a novel, potent and specific inhibitor of PKCβ (protein kinase C) with potential antidiabetic activity. It competitively and reversibly inhibits PKCβ1 and PKCβ2 with IC50 values of 4.7 and 5.9 nM respectively. It has the usefulness to treat diabetic nephropathy and diabetic macular edem. LY333531 strikingly decreases the chance of HUVEC survival and the effect of LY333531 on apoptotic cell death in HUVEC significantly increases compared with the AGEs group. Blockade of PKC-beta up-regulates the expression of Bax and Bad proteins and down-regulates the expression of Bcl-2 protein. Moreover, LY333531 reduces the ratio of Bcl-2/Bax.

Biological Activity I Assay Protocols (From Reference)
ln Vitro
Ruboxistaurin is a PKCβ benchmark that is both selective and ATP-competitive. Its IC50s for PKCβI and PKCβII are 4.7 and 5.9 nM, respectively. It also exhibits modest inhibition of PKCη (IC50: 52 nM), PKCα (IC50: 360 nM), PKCγ (IC50: 300 nM), and PKCδ (IC50: 250 nM). It has no effect on PKC z (IC50: >100 μM). Significantly inhibiting pivoted monocyte apoptosis at concentrations indistinguishable from near labeling of endothelial cells by monocytes under NG circumstances was ruboxistaurin (10 and 400 nM). Both endothelial cell proliferation and marker molecule expression are unaffected by rutobistatin (10 and 400 nM) [2]. Human glomerular endothelial (HRGEC) vitality induced by high gradients (HG) is decreased by rutosistaurin (LY333531; 10 nM), which also prevents the increase in swiprosin-1 in HRGEC with HG [3].
ln Vivo
In diabetic mice, ruboxistaurin (1 mg/kg; 8 weeks) dramatically decreased the overexpression of swiprosin-1 and GEC while also improving glomerular damage. Ruboxistaurin has the ability to efficiently inhibit the expression of PARP, cleaved-caspase9, cleaved-caspase3, and Bax/Bcl-2 in diabetic mice [3]. The oral dose of rutinistaurin (0.1–10.0 mg/kg) dramatically lowers the amount of leukocytes in the diabetic microcirculation [4].
Animal Protocol
Animal/Disease Models: Rat[4]
Doses: 0.1, 1.0 or 10.0 mg/kg
Route of Administration: Po
Experimental Results: Dramatically diminished the number of leukocytes retained in the retinal microcirculation of diabetic rats.
ADME/Pharmacokinetics
Metabolism / Metabolites
Ruboxistaurin has known human metabolites that include N-desmethyl LY333531.
References

[1]. (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta. J Med Chem. 1996;39(14):2664-2671.

[2]. Ruboxistaurin: LY 333531. Drugs R D. 2007;8(3):193-199.

[3]. The beta-specific protein kinase C inhibitor ruboxistaurin (LY333531) suppresses glucose-induced adhesion of human monocytes to endothelial cells in vitro. J Diabetes Sci Technol. 2007 Nov;1(6):929-35.

[4]. PKC-beta inhibitor (LY333531) attenuates leukocyte entrapment in retinal microcirculation of diabetic rats. Invest Ophthalmol Vis Sci. 2000 Aug;41(9):2702-6.

Additional Infomation
Ruboxistaurin has been investigated for the basic science of Type 2 Diabetes Mellitus and Type 1 Diabetes Mellitus.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C28H28N4O3
Molecular Weight
468.55
Exact Mass
468.216
CAS #
169939-94-0
Related CAS #
Ruboxistaurin mesylate;192050-59-2;Ruboxistaurin hydrochloride;169939-93-9
PubChem CID
153999
Appearance
Brown to reddish brown solid powder
Density
1.34g/cm3
Boiling Point
744.4ºC at 760mmHg
Flash Point
404ºC
Vapour Pressure
4.93E-22mmHg at 25°C
Index of Refraction
1.695
LogP
3.789
Hydrogen Bond Donor Count
1
Hydrogen Bond Acceptor Count
4
Rotatable Bond Count
2
Heavy Atom Count
35
Complexity
872
Defined Atom Stereocenter Count
1
SMILES
CN(C[C@@H]1CCN2C=C(C3=C(C(NC3=O)=O)C4=CN(C5=CC=CC=C45)CCO1)C6=CC=CC=C62)C
InChi Key
ZCBUQCWBWNUWSU-SFHVURJKSA-N
InChi Code
InChI=1S/C28H28N4O3/c1-30(2)15-18-11-12-31-16-21(19-7-3-5-9-23(19)31)25-26(28(34)29-27(25)33)22-17-32(13-14-35-18)24-10-6-4-8-20(22)24/h3-10,16-18H,11-15H2,1-2H3,(H,29,33,34)/t18-/m0/s1
Chemical Name
(12E,32E,7S)-7-((dimethylamino)methyl)-22,25-dihydro-11H,21H,31H-6-oxa-1,3(3,1)-diindola-2(3,4)-pyrrolacyclononaphane-22,25-dione hydrochloride
Synonyms
LY-333531 LY333531 LY 333531
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO : ~25 mg/mL (~53.36 mM)
THF :< 1 mg/mL
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 1.67 mg/mL (3.56 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.1342 mL 10.6712 mL 21.3424 mL
5 mM 0.4268 mL 2.1342 mL 4.2685 mL
10 mM 0.2134 mL 1.0671 mL 2.1342 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
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Calculation results

Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
             (2) Be sure to add the solvent(s) in order.

Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02769611 WITHDRAWN Drug: Ruboxistaurin Heart Failure University of Tennessee 2017-06-28 Phase 1
Phase 2
NCT00190970 COMPLETED Drug: Ruboxistaurin Diabetic Neuropathy Chromaderm, Inc. 2004-10 Phase 2
NCT00133952 COMPLETEDWITH RESULTS Drug: Ruboxistaurin
Drug: Placebo
Diabetic Macular Edema Chromaderm, Inc. 2005-08 Phase 3
NCT00266695 COMPLETEDWITH RESULTS Drug: Ruboxistaurin Diabetic Retinopathy Chromaderm, Inc. 2006-01 Phase 3
NCT00297401 COMPLETED Drug: ruboxistaurin
Drug: placebo
Diabetes Mellitus, Type 1 Chromaderm, Inc. 2006-03 Phase 3
Biological Data
  • Endothelial cells were cultured in different media containing 5.5 and 27.7 mM glucose representing NG and HG conditions. HG cultures reveal decreased cell growth compared to NG cultures, whereas the addition of ruboxistaurin at different concentrations (10 and 400 nM) did not affect cell growth.[3]. Kunt T, et al. The beta-specific protein kinase C inhibitor ruboxistaurin (LY333531) suppresses glucose-induced adhesion of human monocytes to endothelial cells in vitro. J Diabetes Sci Technol. 2007 Nov;1(6):929-35.
  • Compared to normoglycemia, there was a 30.9 ± 5.1% increase of monocyte adhesion after stimulation with 27.7 mM glucose. Coincubation of these hyperglycemic cultures with either a β-specific concentration (10 nM) or a nonspecific concentration (400 nM) of ruboxistaurin was able to suppress monocyte adhesion to levels that were not significantly different from those seen in NG cultures [-7.2 ± 3.1 and -8.1 ± 2.6%, respectively; each not significant (n.s.) vs NG].[3]. Kunt T, et al. The beta-specific protein kinase C inhibitor ruboxistaurin (LY333531) suppresses glucose-induced adhesion of human monocytes to endothelial cells in vitro. J Diabetes Sci Technol. 2007 Nov;1(6):929-35.
  • Stimulation of endothelial cells with 27.7 mM glucose (HG) did not modify expression of the investigated adhesion molecules (VCAM-1, ICAM-1, and E-selectin) compared to endothelial cells grown in medium containing 5.5 mM glucose (data not shown). Coincubation with a β-specific (10 nM) and a nonspecific (400 nM) concentration of ruboxistaurin did not change the endothelial expression of adhesion molecules, as shown by means of a chemiluminescence assay (not significant vs each hyperglycemic control).[3]. Kunt T, et al. The beta-specific protein kinase C inhibitor ruboxistaurin (LY333531) suppresses glucose-induced adhesion of human monocytes to endothelial cells in vitro. J Diabetes Sci Technol. 2007 Nov;1(6):929-35.
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