| Size | Price | Stock | Qty |
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| 10mg |
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| 25mg |
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| 50mg |
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Purity: ≥98%
BMS-199264 hydrochloride is a novel and potent inhibitor of the ATP hydrolase activity of mitochondrial F1F0 ATP synthase. It has no affect on the ATP synthase function of F1F0. In isolated rat hearts, BMS-199624 blocks depletion of ATP levels, and blocks necrosis during ischemia. BMS-191264 decreases cardiac necrosis and improves the recovery of contractile activities after reperfusion.
| Targets |
F1F0 ATP hydrolase (IC50=0.5 μM)
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|---|---|
| ln Vitro |
Shortening the effect period and lowering LDH release, BMS-199264 hydrochloride (1 μM, 3 μM, and 10 μM) increased in wastewater after 25 minutes of whole brain and 30 minutes of reinfusion in a concentration-dependent manner [1]. μM) differ in their impact on the activity of buffer enzymes and ATP synthase, measuring 0.18 μMATP/min/mg and 0.23 μMATP/min/mg, respectively[1].
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| ln Vivo |
Cardiac function data pre- and postischemia (30 min into reperfusion) is shown in table 1. BMS-199264 showed modest preischemic cardiodepression only at the high dose, but unfortunately, this compound is so poorly soluble that the solution was cloudy, and it is likely that this is the cause of the cardiodepression at that concentration. In vehicle-treated hearts, reperfusion did not cause significant recovery of contractile function, which is expected due to the severity of the global ischemia. Interestingly, BMS-199264 caused a concentration-dependent improvement in contractile function, unlike data seen for oligomycin or aurovertin.
BMS-199264 increased the time to onset of contracture in a concentration-dependent manner (Fig. 4). Since contracture is due to rigor bond formation, conservation of ATP can be inferred. LDH release (cumulative during 30 min of reperfusion) was reduced in a concentration-dependent manner, suggesting reduced necrosis (Fig. 4).[1] |
| Enzyme Assay |
The mitochondrial F1F0 ATP synthase is responsible for the majority of ATP production in mammals and does this through a rotary catalytic mechanism. Studies show that the F1F0 ATP synthase can switch to an ATP hydrolase, and this occurs under conditions seen during myocardial ischemia. This ATP hydrolysis causes wasting of ATP that does not produce work. The degree of ATP inefficiently hydrolyzed during ischemia may be as high as 50-90% of the total. A naturally occurring, reversible inhibitor (IF-1) of the hydrolase activity is in the mitochondria, and it has a pH optimum of 6.8. Based on studies with the nonselective (inhibit both synthase and hydrolase activity) inhibitors aurovertin B and oligomycin B reduce the rate of ATP depletion during ischemia, showing that IF-1 does not completely block hydrolase activity. Oligomycin and aurovertin cannot be used for treating myocardial ischemia as they will reduce ATP production in healthy tissue. We generated a focused structure-activity relationship, and several compounds were identified that selectively inhibited the F1F0 ATP hydrolase activity while having no effect on synthase function. One compound, BMS-199264 had no effect on F1F0 ATP synthase function in submitochondrial particles while inhibiting hydrolase function, unlike oligomycin that inhibits both. BMS-199264 selectively inhibited ATP decline during ischemia while not affecting ATP production in normoxic and reperfused hearts. BMS-191264 also reduced cardiac necrosis and enhanced the recovery of contractile function following reperfusion. These data also suggest that the reversal of the synthase and hydrolase activities is not merely a chemical reaction run in reverse.[1]
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| Animal Protocol |
Effect of BMS-199264 on pre- and postischemic cardiac function (left ventricular developed pressure [LVDP] in isolated rat hearts subjected to a 25-min global ischemia followed by a 30-min reperfusion.
Effect of increasing concentrations of the mitochondrial ATP hydrolase inhibitor BMS-199264 on the time to the onset of ischemic contracture and reperfusion cumulative LDH release in isolated rat hearts after a 25-min global ischemia followed by a 30-min reperfusion. BMS-199264 increased the time to contracture and reduced LDH release in a concentration-dependent manner, which was not blocked by glyburide. [1] |
| References | |
| Additional Infomation |
Also unknown is the mechanism by which a small organic molecule such as BMS-199264 can selectively block hydrolase activity. The blocking effect is stereoselective, suggesting a specific “lock and key” mechanism and therefore high selectivity. Since IF-1 is active only under conditions similar to ischemia, selectivity for hydrolase activity is not an issue for this protein. Thus far, the only way we can rationalize the selective action of the small molecule BMS-199264 is by hypothesizing that the switch from ATP synthase to hydrolase activity is not merely a chemical reaction run in reverse but requires a change in enzyme conformation, as suggested by Vinogradov. BMS-199264 may (hypothetically at least) bind only to the conformation seen when the F1F0 ATPase is in hydrolase mode. Of course, this is only a conjecture, and more detailed work is necessary to prove this. The effect of BMS-199264 on F1F0 ATPase function may also be secondary to interaction with a pathway that is important in modulating F1F0 ATPase or even IF-1 function, and we cannot rule this out.
Moving from theory to practice, there are many possibilities for agents that can selectively suppress F1F0 ATP hydrolase function. Before getting into this further, no pharmacokinetic data exist for BMS-199264, therefore oral bioavailability is unknown. BMS-199264 apparently does readily penetrate cell membranes and apparently crossed the mitochondrial inner membrane. For the heart, such agents would be useful for severe ischemia where oxidative phosphorylation is significantly inhibited. This will not happen with chronic stable angina but with a severe heart attack. Therefore, treatment will have to be an adjunctive therapy early into the attack before and/or during surgical intervention. One could envision inclusion of such an inhibitor into the cardioplegic solution during surgery. Inclusion into storage solutions for transplants is another possibility.[1] |
| Molecular Formula |
C26H32CL2N4O4S
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|---|---|
| Molecular Weight |
567.527683258057
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| Exact Mass |
566.152
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| Elemental Analysis |
C, 55.03; H, 5.68; Cl, 12.49; N, 9.87; O, 11.28; S, 5.65
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| CAS # |
186180-83-6
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| Related CAS # |
675833-20-2;186180-83-6 (HCl);
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| PubChem CID |
70202986
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| Appearance |
Typically exists as White to off-white solid at room temperature
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
37
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| Complexity |
841
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC1([C@H]([C@@H](C2=C(O1)C=CC(=C2)S(=O)(=O)N3CCCCC3)N(CC4=NC=CN4)C5=CC=C(C=C5)Cl)O)C.Cl
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| InChi Key |
CKNXQCNQMADQCI-KGQXAQPSSA-N
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| InChi Code |
InChI=1S/C26H31ClN4O4S.ClH/c1-26(2)25(32)24(31(17-23-28-12-13-29-23)19-8-6-18(27)7-9-19)21-16-20(10-11-22(21)35-26)36(33,34)30-14-4-3-5-15-30/h6-13,16,24-25,32H,3-5,14-15,17H2,1-2H3,(H,28,29)1H/t24-,25+/m1./s1
|
| Chemical Name |
(3S,4R)-4-[(4-Chlorophenyl)(1H-imidazol-2-ylmethyl)amino]-3,4-dihydro-2,2-dimethyl-6-(1-piperidinylsulfonyl)-2H-1-Benzopyran-3-ol
hydrochloride
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| Synonyms |
BMS-199264; BMS199264; BMS-199264 (hydrochloride); (3S,4R)-4-[4-chloro-N-(1H-imidazol-2-ylmethyl)anilino]-2,2-dimethyl-6-piperidin-1-ylsulfonyl-3,4-dihydrochromen-3-ol;hydrochloride; SCHEMBL7836701; BMS 199264; BMS-199264 hydrochloride
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 1.7620 mL | 8.8101 mL | 17.6202 mL | |
| 5 mM | 0.3524 mL | 1.7620 mL | 3.5240 mL | |
| 10 mM | 0.1762 mL | 0.8810 mL | 1.7620 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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