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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.
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) |
Biological Activity
| 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. |
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 |