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Purity: ≥98%
PD 151746 (PD-151746) is a novel, potent, selective, and cell-permeable calpain inhibitor with important biological activity. It has a selectivity for u-calpain (Ki = 0.26 ± 0.03 μM) that is roughly 20 times higher than that of m-calpain (Ki = 5.33 ± 0.77 μM), and it inhibits calpain with a Ki of 0.26 μM for μ-Calpain. PD151746 completely inhibited the fragmentation of calmodulin-dependent protein kinase II-α (CaMPK-IIα) and nitric oxide synthase (nNOS), which were cleaved by calpain, and significantly inhibited NMDA-induced α-spectrin breakdown product (SBDP) of 145 kDa. PD 151746, an μ-calpain inhibitor, reduces the cytotoxicity caused by oxLDL.
| Targets |
μ-Calpain (IC50 = 260 nM); m-calpain (IC50 = 5.33 μM)
PD151746 targets μ-calpain (Ki = 0.26 ± 0.03 μM) and m-calpain (Ki = 5.33 ± 0.77 μM). It also shows weak inhibition of calmodulin-stimulated calcineurin (Ki = 84.54 ± 3.81 μM) and does not significantly inhibit cathepsin B (Ki > 200 μM), papain (Ki > 500 μM), trypsin (Ki > 500 μM), thermolysin (Ki > 500 μM), or basal calcineurin (Ki > 200 μM).[1] |
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| ln Vitro |
PD151746 efficiently reduces the SLLVY-AMC hydrolysis brought on by maitotoxin in SY5Y cells. (Source: ) PD 151746 reduces the cytotoxicity of oxidized low-density lipoprotein (oxLDL) in HMEC-1 cells.[2]
PD151746 inhibits μ-calpain with a Ki of 0.26 ± 0.03 μM and m-calpain with a Ki of 5.33 ± 0.77 μM; complete inhibition of m-calpain is not achieved even at 200 μM. It shows high selectivity for calpains over other proteases: cathepsin B (Ki > 200 μM), papain (Ki > 500 μM), trypsin (Ki > 500 μM), thermolysin (Ki > 500 μM). In human neuroblastoma SH-SY5Y cells, pretreatment with 10 μM PD151746 effectively attenuates maitotoxin-induced hydrolysis of the fluorogenic calpain substrate SLLVY-AMC. PD151746 inhibits the calmodulin-stimulated component of calcineurin with a Ki of 84.54 ± 3.81 μM, while having no effect on basal calcineurin activity (Ki > 200 μM).[1] |
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| ln Vivo |
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| Enzyme Assay |
PD151746 is a calpain inhibitor that exhibits a 20-fold selectivity for u-calpain (Ki = 0.26 ± 0.03 μM) compared to m-calpain (Ki = 5.33 ± 0.77 μM).
The inhibitory activity of PD151746 against μ-calpain and m-calpain was evaluated using a casein microplate assay. The reaction mixture contained 0.5 mg/mL casein, 20 mM DTT, 50 mM Tris-HCl (pH 7.4), purified μ-calpain (human erythrocytes) or m-calpain (rabbit skeletal muscle), various concentrations of inhibitor, and 4 mM CaCl2 in a total volume of 250 μL. After incubation for 60 min at 25°C, colorimetric development was measured at 595 nm. IC50 values were generated from plots of percentage inhibition versus log(inhibitor), and apparent Ki values were calculated according to Cheng and Prusoff.[1] |
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| Cell Assay |
PD151746 prevented serum/potassium (S/K) withdrawal-induced apoptosis in cerebellar granule cells by 29% by blocking calpain. Moreover, PD151746 reduced caspase-3 activity, cdk5/p25 formation, and the rise in MEF2 phosphorylation. PD151746 dramatically decreased insulin-stimulated glycogen synthesis in human hepatoma G2 cells while increasing protein tyrosine phosphatase-ε (PTPε), suggesting that calpain was a key player in the regulation of insulin-stimulated glycogen synthesis. PD151746 elevated cytoplasmic free Ca2+ ([Ca2+]I) in HEK-293 cells expressing human formyl peptide receptor (hFPR) or hFPR-like 1 (hFPRL1).
Human neuroblastoma SH-SY5Y cells were grown to confluency (about 2 million per well) in 12-well plates with DMEM supplemented with 10% fetal bovine serum, 100 units/mL penicillin, 100 μg/mL streptomycin, and 2.5 μg/mL fungizone. Prior to the experiment, confluent cultures were washed three times with serum-free DMEM. Calpain inhibitors (including PD151746) were added for 1 hour of preincubation. Then medium containing the fluorogenic substrate SLLVY-AMC (80 μM final concentration) was added, and maitotoxin (0.1 nM) was added if desired. The plates were incubated at room temperature, and fluorescence (excitation 380 nm, emission 460 nm) was measured every 15-30 minutes up to 120 minutes using a fluorescence plate reader. PD151746 at 10 μM significantly inhibited maitotoxin-induced SLLVY-AMC hydrolysis.[1] |
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| Animal Protocol |
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| References | |||
| Additional Infomation |
PD151746 (3-(5-fluoro-3-indolyl)-2-mercapto-(Z)-2-propenoic acid) is a representative mercaptoacrylic acid derivative. The double bond in its structure is critical for calpain inhibitory action, as a saturated analog (PD145305) is inactive up to 500 μM. Unmodified sulfhydryl and carboxylic acid groups are also necessary for inhibition. PD151746 shows 20-fold selectivity for μ-calpain over m-calpain and does not act as a simple calcium chelator (low affinity for free calcium ions). Its inhibitory mode is uncompetitive with respect to substrate, and it interacts with the calcium-binding domains of calpain rather than the active site.[1]
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| Molecular Formula |
C11H8FNO2S
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| Molecular Weight |
237.25
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| Exact Mass |
237.026
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| Elemental Analysis |
C, 55.69; H, 3.40; F, 8.01; N, 5.90; O, 13.49; S, 13.51
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| CAS # |
179461-52-0
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| Related CAS # |
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| PubChem CID |
5353866
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| Appearance |
Light yellow to brown solid powder
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| Density |
1.525±0.06 g/cm3
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| LogP |
2.662
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
16
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| Complexity |
321
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(O)/C(S)=C/C1=CNC2=C1C=C(F)C=C2
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| InChi Key |
HWMQHECFXSVZGN-KMKOMSMNSA-N
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| InChi Code |
InChI=1S/C11H8FNO2S/c12-7-1-2-9-8(4-7)6(5-13-9)3-10(16)11(14)15/h1-5,13,16H,(H,14,15)/b10-3-
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| Chemical Name |
(Z)-3-(5-fluoro-1H-indol-3-yl)-2-sulfanylprop-2-enoic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.03.00
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.2150 mL | 21.0748 mL | 42.1496 mL | |
| 5 mM | 0.8430 mL | 4.2150 mL | 8.4299 mL | |
| 10 mM | 0.4215 mL | 2.1075 mL | 4.2150 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.
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.
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