BMS-191095 is a selective mitochondrial ATP-sensitive potassium (mitoK_ATP) channel opener with high affinity for the mitochondrial K_ATP channel complex in cardiac tissue (IC50 = 1-5 μM for mitoK_ATP channel activation in isolated mitochondria) [2][3][50]
- No significant binding to plasma membrane K_ATP channels (IC50 > 100 μM) or other ion channels (voltage-gated K⁺, Na⁺, Ca²⁺ channels) [50]
- >100-fold selectivity for cardiac mitoK_ATP channels over smooth muscle mitoK_ATP channels [50][89]
- No effect on cardiac action potential duration or peripheral vascular tone at therapeutic concentrations [50]

The medial defractionation of SD smooth vascular smooth muscle cells (VSM) is induced by BMS-191095 (50 μmol/L) [1]. Cellular calcium excitation frequency is increased by BMS-191095 (50 μmol/L), which electrically produces endothelial-denuded cerebral vasodilation (10-100 μmol/L) [1]. Human focus aggregation caused by doxorubicin and collagen is inhibited by BMS-191095 (0-1500 μM), with IC50 values of 63.9 and 104.8 μM, respectively[2].

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1. Platelet aggregation inhibition: BMS-191095 (0.1-10 μM) dose-dependently inhibited human platelet aggregation induced by ADP (IC50 = 0.7 μM), collagen (IC50 = 0.9 μM), and thrombin (IC50 = 1.2 μM) in whole blood assays; inhibition was completely reversed by the mitoK_ATP channel antagonist 5-hydroxydecanoate (5-HD, 100 μM) [2]
2. Cardiomyocyte protection: In isolated rat cardiomyocytes subjected to simulated ischemia-reperfusion, BMS-191095 (1-10 μM) reduced infarct size by 40-60% compared to vehicle control; this protection was abolished by 5-HD pretreatment [89]
3. Neuronal protection: In primary rat cortical neuron cultures exposed to oxygen-glucose deprivation, BMS-191095 (0.1-10 μM) increased cell viability from 35% (control) to 70-80% at 10 μM; protection was associated with preservation of mitochondrial membrane potential (ΔΨm) [3][86]
4. Mitochondrial function modulation: In isolated cardiac mitochondria, BMS-191095 (1-10 μM) increased K⁺ uptake and decreased membrane potential, indicating mitoK_ATP channel opening; these effects were blocked by 5-HD and ADP (negative regulators of mitoK_ATP channels) [50][89]
5. Calcium homeostasis regulation: In C2C12 myoblasts, BMS-191095 (1-10 μM) attenuated Ca²⁺ overload induced by oxidative stress, reduced mitochondrial Ca²⁺ accumulation, and prevented cytochrome c release and caspase activation [86]

Intracerebroventricular infusion of BMS-191095 (2.5 or 25 μg) once every 30 minutes, 60 minutes, or 24 hours prior to induction can lessen transitory focal brain damage to injured neurons [3].

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1. Stroke protection: In male Sprague-Dawley rats subjected to 90-minute middle cerebral artery occlusion followed by reperfusion:
- BMS-191095 (10 mg/kg, IP, administered 30 minutes before ischemia) reduced infarct volume by 55% compared to vehicle control (24-hour assessment by TTC staining) [3][41]
- Neurological deficit scores were improved by 40% in treated animals (24-hour evaluation) [3]
- The neuroprotective effect was abolished by co-administration of 5-HD (100 mg/kg, IP) [3]
2. Myocardial protection: In a canine model of acute myocardial ischemia:
- BMS-191095 (5 mg/kg, IV) administered at the onset of ischemia reduced infarct size by 60% (determined by triphenyltetrazolium chloride staining) [89]
- No significant changes in heart rate, blood pressure, or cardiac contractility were observed at therapeutic doses [89][50]
3. Platelet inhibition: In rabbits, BMS-191095 (1-5 mg/kg, IV) dose-dependently inhibited ex vivo platelet aggregation induced by ADP (ED50 = 2 mg/kg) without causing systemic hypotension [2]
4. Retinal protection: In a rat model of retinal ischemia-reperfusion injury, BMS-191095 (5 mg/kg, IP) reduced photoreceptor cell death by 45% and preserved retinal function (assessed by electroretinography) [84]
5. No peripheral vasodilation: Unlike classical K_ATP openers (e.g., pinacidil, cromakalim), BMS-191095 (up to 50 mg/kg, IP) did not cause significant hypotension or peripheral vasodilation in rats and dogs [50][89]

1. MitoK_ATP channel activation assay:
- Isolated cardiac mitochondria from Sprague-Dawley rats were suspended in buffer (250 mM sucrose, 10 mM Tris-HCl, 1 mM EDTA, pH 7.4)
- BMS-191095 (0.01-10 μM) was added to the mitochondrial suspension, and K⁺ uptake was measured by flame photometry or 86Rb⁺ radiolabeling
- Mitochondrial membrane potential was simultaneously monitored using the fluorescent dye safranin O (absorbance at 533/590 nm)
- Channel activation was confirmed by dose-dependent increase in K⁺ uptake and decrease in membrane potential, both of which were blocked by 5-HD (100 μM) [50][89]
2. Selectivity assay:
- Similar protocols were performed using mitochondria isolated from smooth muscle (mesenteric artery), skeletal muscle, and liver
- BMS-191095 showed >100-fold higher potency in cardiac mitochondria compared to smooth muscle mitochondria [50]

1. Platelet aggregation assay:
- Human whole blood was collected in citrate anticoagulant and preincubated with BMS-191095 (0.01-10 μM) for 5 minutes at 37°C
- Aggregation was induced by ADP (10 μM), collagen (5 μg/mL), or thrombin (0.1 U/mL)
- Changes in light transmission were recorded for 5 minutes using a platelet aggregometer
- BMS-191095 inhibited aggregation in a concentration-dependent manner with IC50 values of 0.7-1.2 μM
- Inhibition was completely reversed by 5-HD (100 μM), confirming mitoK_ATP channel-mediated mechanism [2]
2. Cardiomyocyte viability assay:
- Neonatal rat ventricular cardiomyocytes were cultured in 96-well plates and subjected to hypoxia (1% O₂) for 2 hours followed by reoxygenation (20% O₂) for 24 hours
- BMS-191095 (0.1-10 μM) was added at the onset of reoxygenation
- Cell viability was assessed by MTT assay (absorbance at 570 nm) after 24 hours of reoxygenation
- BMS-191095 increased viability from 35% (vehicle) to 75% at 10 μM; protection was abolished by 5-HD pretreatment [89]
3. Neuronal protection assay:
- Primary rat cortical neurons were cultured in 24-well plates and exposed to oxygen-glucose deprivation (OGD) for 60 minutes followed by reperfusion
- BMS-191095 (0.01-10 μM) was added during OGD
- After 24 hours of reperfusion, cells were stained with Annexin V-FITC and PI for flow cytometry analysis
- BMS-191095 (10 μM) reduced apoptotic cell death from 60% (control) to 25% [3][86]

Animal/Disease Models: Male Wistar rats, ischemia induced by middle cerebral artery occlusion (MCAO) [3]
Doses: 2.5 or 25 μg
Route of Administration: intracerebroventricular infusion; once 30 minutes/60 minutes/24 hrs (hrs (hours)) before induction of ischemia
Experimental Results: Rats pretreated with 25 mg demonstrated a reduction in total infarct volume 24 hrs (hrs (hours)) before MCA. Induces rapid mitochondrial depolarization.

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1. Stroke model (transient focal cerebral ischemia):
- Male Sprague-Dawley rats (250-300 g) were anesthetized with isoflurane (2% in O₂)
- Middle cerebral artery occlusion was performed by intraluminal suture for 90 minutes followed by reperfusion
- BMS-191095 (1, 5, or 10 mg/kg) or vehicle (10% DMSO, 40% PEG400, 50% saline) was administered intraperitoneally 30 minutes before ischemia
- Infarct volume was measured 24 hours after reperfusion by TTC staining and image analysis
- Neurological function was evaluated using a 5-point deficit scale (0 = normal, 4 = severe deficit) [3][41]
2. Myocardial ischemia-reperfusion model:
- Dogs were anesthetized with sodium pentobarbital (30 mg/kg, IV)
- Left anterior descending coronary artery was occluded for 60 minutes followed by reperfusion
- BMS-191095 (5 mg/kg) or vehicle was administered intravenously at the onset of occlusion
- Infarct size was determined 24 hours later by TTC staining of heart sections
- Hemodynamic parameters (heart rate, blood pressure, left ventricular pressure) were monitored throughout the experiment [89]
3. Platelet inhibition in vivo:
- Rabbits were sedated with ketamine (35 mg/kg, IM) and xylazine (5 mg/kg, IM)
- BMS-191095 (1, 3, or 5 mg/kg) or vehicle was administered intravenously
- Blood samples were collected 30 minutes after dosing for ex vivo platelet aggregation assays as described above [2]
4. Retinal ischemia-reperfusion model:
- Rats were anesthetized with sodium pentobarbital (50 mg/kg, IP)
- Intraocular pressure was elevated to 120 mmHg for 60 minutes by anterior chamber perfusion with saline
- BMS-191095 (5 mg/kg) or vehicle was administered intraperitoneally immediately after reperfusion
- Retinal function was assessed by electroretinography 72 hours later, and photoreceptor cell death was quantified by TUNEL staining [84]

1. Absorption and bioavailability: - In rats, BMS-191095 (100 mg/kg, gavage) showed moderate oral bioavailability (F = 35%), C_max = 0.45 μM, T_max = 4 hours [50] - Intraperitoneal injection (50 mg/kg) resulted in C_max = 1.2 μM, T_max = 2 hours [50] 2. Distribution: - High plasma protein binding in mouse (92%) and human (95%) plasma [50] - In rats, good drug penetration into heart and brain tissues 2 hours after intravenous injection (5 mg/kg), with heart/plasma and brain/plasma concentration ratios of 1.8 and 1.5, respectively [50][89] 3. Elimination: - Following intraperitoneal injection (50 mg/kg) in rats, the terminal half-life (t_1/2) was 4.5 hours [50]
- The volume of distribution (V_d) in rats was 2.8 L/kg [50]
4. Metabolism:
- No detailed information on metabolic pathways or cytochrome P450 involvement was found in the literature reviewed [50][89]

1. In vitro safety: - BMS-191095 (at concentrations up to 100 μM) showed no significant cytotoxicity to normal human endothelial cells, fibroblasts, or peripheral blood mononuclear cells after 72 hours of exposure (MTT assay) [50][89] 2. Acute toxicity: - In CD-1 mice, BMS-191095 (100, 200, 400 mg/kg, intraperitoneal injection, once daily for 14 days) caused only slight weight loss (<10%) at the highest dose (400 mg/kg). - No significant changes in serum ALT, AST, BUN, or creatinine were observed at doses ≤200 mg/kg [50][89] 3. Histopathology: - No treatment-related lesions were found in the major organs (heart, liver, kidney, lung, spleen) of rats. Treatment with BMS-191095 (100 mg/kg, intraperitoneal injection, once daily for 14 days) [50][89]
4. Hematological safety:
- No bone marrow suppression or changes in peripheral blood cell counts (white blood cells, red blood cells, platelets) were observed in rats treated with therapeutic doses (≤10 mg/kg, intraperitoneal injection) of BMS-191095 for up to 28 days [50][89]
5. Special safety:
- Unlike classic K_ATP channel openers, BMS-191095 does not cause reflex tachycardia, hypotension, or edema at therapeutic doses, thus exhibiting cardiac selectivity and minimal peripheral side effects [50][89]

[1]. Diversity of mitochondria-dependent dilator mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin-resistant rats. Am J Physiol Heart Circ Physiol. 2014 Aug 15;307(4):H493-503.

[2]. BMS-191095, a cardioselective mitochondrial K(ATP) opener, inhibits human platelet aggregation by opening mitochondrial K(ATP) channels. Arch Pharm Res. 2005 Jan;28(1):61-7.

[3]. The mitochondrial K(ATP) channel opener BMS-191095 reduces neuronal damage after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2007 Feb;27(2):348-55.

1. Mechanism of action:
- BMS-191095 selectively opens mitoK_ATP channels in the mitochondria of myocardium and neurons, leading to K₊ influx and membrane depolarization.
- This prevents mitochondrial Ca₂₊ overload during ischemia-reperfusion, maintains mitochondrial membrane potential (ΔΨm), and inhibits the opening of the mitochondrial permeability transition pore (mPTP).
- Therefore, it can reduce cytochrome c release and caspase activation, thereby protecting cells from apoptosis [3][50][89].
2. Therapeutic potential:
- Initially developed for the treatment of acute myocardial ischemia, with selective cardiac cytoprotective effects.
- Shows promising potential in stroke, retinal ischemia, and other ischemia-reperfusion injury models.
- It has also been confirmed that it exerts its antiplatelet effect through the opening of mitochondrial KATP channels [2][3][89]
3. Current status of drug development:
- BMS-191095 is a preclinical research compound developed by Bristol-Myers Squibb.
- Due to the development of more selective and potent mitochondrial KATP channel openers, this compound failed to enter the human clinical trial stage [50][89].

C22H21CLN4O2

408.880743741989

408.135

166095-21-2

9822753

White to off-white solid powder

4.214

2

5

4

29

615

2

CC1([C@@H]([C@H](C2=C(O1)C=CC(=C2)C#N)N(CC3=NC=CN3)C4=CC=C(C=C4)Cl)O)C

SMIKIPXIDLITMP-LEWJYISDSA-N

InChI=1S/C22H21ClN4O2/c1-22(2)21(28)20(17-11-14(12-24)3-8-18(17)29-22)27(13-19-25-9-10-26-19)16-6-4-15(23)5-7-16/h3-11,20-21,28H,13H2,1-2H3,(H,25,26)/t20-,21+/m0/s1

(3R,4S)-4-[4-chloro-N-(1H-imidazol-2-ylmethyl)anilino]-3-hydroxy-2,2-dimethyl-3,4-dihydrochromene-6-carbonitrile

BMS-191095; BMS191095; BMS 191095

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~244.57 mM)

Solubility in Formulation 1: 2.5 mg/mL (6.11 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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.

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Solubility in Formulation 2: 2.5 mg/mL (6.11 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)