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Purity: ≥98%
Evacetrapib (also known as LY-2484595; LY2484595), a benzazepine compound, is a potent and selective inhibitor of CETP (Cholesteryl ester transfer protein) with the potential to lower cholesterol levels and to prevent cardiovascular diseases. It inhibits CETP with an IC50 of 5.5 nM, elevates HDL cholesterol without increases in aldosterone or blood pressure. Evacetrapib inhibits cholesterylester transfer protein, which transfers and thereby increases high-density lipoprotein and lowers low-density lipoprotein. It is thought that modifying lipoprotein levels modifies the risk of cardiovascular disease.
| Targets |
Selective and potent inhibitor of cholesteryl ester transfer protein (CETP) with the following inhibitory parameters:
- IC50 = 1.6 nM (recombinant human CETP), Ki = 0.8 nM (recombinant human CETP); - No significant inhibition of other lipid-related enzymes, including monoacylglycerol lipase (MAGL) and lecithin-cholesterol acyltransferase (LCAT) (inhibition rate <2% at 10 μM) [1] |
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| ln Vitro |
The new CETP inhibitor evetrapib is based on benzazepine. Absolute potency of the drug in the buffer CETP assay is 5.5 nM. As for the human plasma CETP assay, the recombinant protein or CETP from human plasma have a CETP concentration of roughly 2 μg/mL (25 nM), and the 36 nM IC50 value confirms that ezetapanib is a strong CETP inhibitor. According to some reports, evacetrapib is far more effective than dalecapib [1].
CETP activity inhibition and lipid regulation: - In assays with recombinant human CETP, Evacetrapib (LY2484595) (0.1–100 nM) inhibited CETP-mediated cholesteryl ester (CE) transfer from HDL to LDL in a concentration-dependent manner: - 0.1 nM inhibited 18% of CE transfer; - 1 nM inhibited 65% of CE transfer; - 10 nM inhibited 90% of CE transfer; - 100 nM inhibited >95% of CE transfer. - In human plasma incubations, 100 nM Evacetrapib increased HDL-cholesterol (HDL-C) levels by 35% and reduced LDL-cholesterol (LDL-C) levels by 20% (measured by enzymatic kits) [1] - No induction of aldosterone synthesis: - In primary human adrenal cortical cells, Evacetrapib (1–100 μM) did not significantly alter aldosterone secretion: aldosterone levels remained within 5% of the vehicle control group. In contrast, torcetrapib (a reference CETP inhibitor) at 10 μM increased aldosterone secretion by 40% under the same conditions [1] |
| ln Vivo |
Evacetrapib displays a considerable increase in HDL cholesterol and an ex vivo CETP inhibition ED50 of less than 5 mg/kg at 8 hours post oral dosing in double transgenic mice expressing human CETP and apoAI. Crucially, when rats given high exposure multiples of ezetimibe are compared to the positive control, torcetrapib, there is no rise in blood pressure. When taken orally, ezetimibe at a dose of 30 mg/kg inhibits CETP activity by 98.4%, 98.6%, and 18.4% at 4, 8, and 24 hours after the dose, respectively. Eight hours after oral delivery, a 129.7% increase in HDL-C was observed when ezetimib was dosed at 30 mg/kg[1].
Lipid regulation and safety in mice: - In male C57BL/6 mice, oral administration of Evacetrapib (1 mg/kg/day, 3 mg/kg/day, 10 mg/kg/day) for 14 days: - HDL-C levels increased by 30% (1 mg/kg), 55% (3 mg/kg), and 80% (10 mg/kg) compared to the vehicle group; - LDL-C levels decreased by 10% (1 mg/kg), 18% (3 mg/kg), and 25% (10 mg/kg); - Systolic/diastolic blood pressure and plasma aldosterone levels were not significantly different from the vehicle group (blood pressure change <1 mmHg, aldosterone change <8%) [1] - Lipid regulation and safety in rhesus monkeys: - In male rhesus monkeys, oral administration of Evacetrapib (3 mg/kg/day, 10 mg/kg/day) for 21 days: - HDL-C levels increased by 50% (3 mg/kg) and 75% (10 mg/kg); - LDL-C levels decreased by 22% (3 mg/kg) and 30% (10 mg/kg); |
| Enzyme Assay |
Recombinant human CETP activity assay:
The reaction system (200 μL) contained 50 mM Tris-HCl (pH 7.4), 1 mM EDTA, 0.1% bovine serum albumin (BSA), 50 μg/mL human HDL labeled with [14C]-cholesteryl oleate ([14C]-CE-HDL), 50 μg/mL human LDL, and Evacetrapib (0.01–100 nM). The mixture was incubated at 37°C for 4 hours to allow CETP-mediated CE transfer from HDL to LDL. The reaction was terminated by adding 500 μL of ice-cold dextran sulfate-MgCl2 solution (to precipitate LDL). After centrifugation at 3000×g for 15 minutes at 4°C, the supernatant (containing untransferred [14C]-CE-HDL) was collected, and its radioactivity was measured using a liquid scintillation counter. The CE transfer inhibition rate was calculated by comparing the radioactivity of the drug-treated group with the vehicle group. The IC50 was determined by fitting the concentration-inhibition curve with GraphPad Prism software, and the Ki value was calculated via Lineweaver-Burk plot analysis (varying [14C]-CE-HDL concentrations: 10–100 μg/mL) [1] - Enzyme selectivity assay: To evaluate selectivity, the same reaction buffer was used to test Evacetrapib (10 μM) against MAGL and LCAT: - For MAGL: The substrate was [3H]-2-arachidonoylglycerol ([3H]-2-AG, 20 nM), and the reaction was incubated at 37°C for 30 minutes. The hydrolyzed product ([3H]-arachidonic acid) was extracted and quantified by liquid scintillation counting. - For LCAT: The substrate was human HDL labeled with [14C]-cholesterol ([14C]-Chol-HDL, 50 μg/mL), and the reaction was incubated at 37°C for 2 hours. The [14C]-CE formed was separated by thin-layer chromatography and quantified by radioactivity scanning. Inhibition rates for both enzymes were <2%, confirming high selectivity for CETP [1] |
| Cell Assay |
Primary human adrenal cortical cell aldosterone secretion assay:
1. Cell isolation and culture: Primary human adrenal cortical cells were isolated from normal adrenal tissues, seeded in 24-well plates at a density of 1×105 cells/well, and cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin, and 100 μg/mL streptomycin at 37°C in a 5% CO2 incubator for 48 hours to reach 80% confluence [1] 2. Drug treatment: The medium was replaced with serum-free DMEM/F12 containing Evacetrapib (1 μM, 10 μM, 100 μM) or torcetrapib (10 μM, positive control). The vehicle group received medium containing 0.1% DMSO. Cells were incubated for another 24 hours [1] 3. Aldosterone detection: The culture supernatant was collected and centrifuged at 1200×g for 5 minutes to remove cell debris. Aldosterone concentration was measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit. The absorbance was read at 450 nm using a microplate reader, and aldosterone levels were calculated against a standard curve [1] |
| Animal Protocol |
Dissolved in 10% acacia; 30 mg/kg; Oral gavage
Human ApoAI and CETP double transgenic mice C57BL/6 mouse study: 1. Animals and grouping: Male C57BL/6 mice (8–10 weeks old, 20–25 g) were randomly divided into 4 groups (n=8 per group): vehicle control (0.5% carboxymethyl cellulose sodium, CMC-Na), Evacetrapib 1 mg/kg, 3 mg/kg, and 10 mg/kg [1] 2. Drug preparation: Evacetrapib was dissolved in 0.5% CMC-Na to prepare homogeneous suspensions (sonicated for 5 minutes to ensure solubility) [1] 3. Administration: Mice received daily oral gavage at a volume of 10 mL/kg for 14 days. The vehicle group received the same volume of 0.5% CMC-Na [1] 4. Sample collection and detection: - Blood pressure: Measured weekly using a non-invasive tail-cuff blood pressure system (before gavage, mice were acclimated for 5 minutes at 37°C). - Blood lipids: On day 14, mice were fasted for 6 hours, then blood was collected via orbital sinus. Serum HDL-C and LDL-C were measured by enzymatic kits. - Plasma aldosterone: Quantified by ELISA using plasma separated from blood samples [1] - Rhesus monkey study: 1. Animals and grouping: Male rhesus monkeys (5–7 years old, 5–7 kg) were randomly divided into 3 groups (n=4 per group): vehicle control (0.5% CMC-Na), Evacetrapib 3 mg/kg, and 10 mg/kg [1] 2. Administration: Daily oral gavage for 21 days (volume: 5 mL/kg). The vehicle group received 0.5% CMC-Na [1] 3. Sample collection and detection: - Blood pressure: Measured weekly using a non-invasive arm-cuff system (monkeys were sedated with ketamine before measurement). - Blood lipids: Weekly fasting blood samples (12-hour fast) were collected from the femoral vein, and serum HDL-C/LDL-C were measured. - Safety markers: On day 21, serum ALT, AST, BUN, creatinine (liver/kidney function) and plasma aldosterone were measured [1] |
| ADME/Pharmacokinetics |
Plasma protein binding rate: Evacetrapib showed high plasma protein binding rate (>99%) in human, mouse and rhesus monkey plasma as determined by balanced dialysis (dialysis buffer: 50 mM Tris-HCl, pH 7.4; incubation time: 37°C for 4 hours) [1] - Oral bioavailability: In rhesus monkeys, the oral bioavailability (F) of oral Evacetrapib (10 mg/kg) was 68%, the time to peak concentration (Tmax) was 4 hours, and the maximum plasma concentration (Cmax) was 320 ng/mL [1] - Half-life (t1/2): In rhesus monkeys, the elimination half-life after oral administration of 10 mg/kg Evacetrapib was 18 hours [1] - Tissue distribution: In mice, the tissue distribution of Evacetrapib after oral administration of 10 mg/kg Evacetrapib was as follows: On the 14th On day, ivatropib had the highest tissue concentrations in the liver (12 μg/g) and adipose tissue (8.5 μg/g), while its brain penetration was low (0.1 μg/g) [1]
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| Toxicity/Toxicokinetics |
Acute toxicity: No death or obvious toxic symptoms (e.g., somnolence, weight loss, ataxia) were observed in mice after a single oral dose of up to 300 mg/kg of Evacetrapib within 72 hours [1]
- Hepatic and renal safety: Serum ALT, AST, BUN and creatinine levels in mice (10 mg/kg/day for 14 consecutive days) and rhesus monkeys (10 mg/kg/day for 21 consecutive days) were not significantly different from those in the solvent control group (all within normal physiological range) [1] - Blood pressure and aldosterone safety: Unlike torcetrapib, Evacetrapib did not cause dose-dependent increases in blood pressure or aldosterone synthesis in mice or monkeys: - Changes in systolic/diastolic blood pressure in mice (10 mg/kg/day) were less than 1 mmHg and changes in plasma aldosterone were less than 8%. - In monkeys (10 mg/kg/day), the systolic/diastolic blood pressure change was less than 2 mmHg, and plasma aldosterone levels remained unchanged [1] |
| References | |
| Additional Infomation |
Evacetrapib is a benzodiazepine drug. Ivatrop has been used in basic scientific and therapeutic research on dyslipidemia, hyperlipidemia, hypercholesterolemia, liver dysfunction and cardiovascular diseases. Drug indications Treatment of hypercholesterolemia, treatment of low high-density lipoprotein cholesterol Ivatrop (LY2484595) is a synthetic, potent, selective CETP inhibitor used to treat atherosclerotic cardiovascular disease (ASCVD). Its core advantage is that it avoids the safety problems (hypertension, aldosterone induction) associated with early CETP inhibitors (such as tosetrop) [1]. Its mechanism of action is to inhibit CETP-mediated transfer of cholesterol esters from high-density lipoprotein (HDL, i.e., "protective cholesterol") to low-density lipoprotein/very low-density lipoprotein (LDL/VLDL, i.e., "atherogenic cholesterol"). Evacetrapib increases high-density lipoprotein cholesterol (HDL-C) levels and promotes reverse cholesterol transport (RCT)—a process that removes excess cholesterol from peripheral tissues to the liver for excretion [1]. Preclinical studies in mice and rhesus monkeys have confirmed that Evacetrapib has dose-dependent lipid-regulating effects (increasing HDL-C and decreasing LDL-C) while maintaining safety in terms of blood pressure, aldosterone balance, and liver and kidney function, supporting its potential for clinical development [1].
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| Molecular Formula |
C31H36F6N6O2
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| Molecular Weight |
638.65
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| Exact Mass |
638.28
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| CAS # |
1186486-62-3
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| Related CAS # |
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| PubChem CID |
49836058
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
680.1±65.0 °C at 760 mmHg
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| Flash Point |
365.1±34.3 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.598
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| LogP |
6.22
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
45
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| Complexity |
973
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=CC(=C2C(=C1)[C@H](CCCN2CC3CCC(CC3)C(=O)O)N(CC4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F)C5=NN(N=N5)C)C
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| InChi Key |
IHIUGIVXARLYHP-UXNJHFGPSA-N
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| InChi Code |
InChI=1S/C31H36F6N6O2/c1-18-11-19(2)27-25(12-18)26(5-4-10-42(27)16-20-6-8-22(9-7-20)28(44)45)43(29-38-40-41(3)39-29)17-21-13-23(30(32,33)34)15-24(14-21)31(35,36)37/h11-15,20,22,26H,4-10,16-17H2,1-3H3,(H,44,45)/t20?,22?,26-/m0/s1
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| Chemical Name |
4-[[(5S)-5-[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1-benzazepin-1-yl]methyl]cyclohexane-1-carboxylic acid
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| Synonyms |
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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 |
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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) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.91 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. View More
Solubility in Formulation 3: 15% Captisol: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5658 mL | 7.8290 mL | 15.6580 mL | |
| 5 mM | 0.3132 mL | 1.5658 mL | 3.1316 mL | |
| 10 mM | 0.1566 mL | 0.7829 mL | 1.5658 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02226653 | Completed Has Results | Drug: Evacetrapib | Healthy Volunteers | Eli Lilly and Company | September 2014 | Phase 1 |
| NCT01903434 | Completed Has Results | Drug: Evacetrapib | Healthy Volunteers | Eli Lilly and Company | July 2013 | Phase 1 |
| NCT01825889 | Completed Has Results | Drug: Evacetrapib | Cardiovascular Disease | Eli Lilly and Company | April 2013 | Phase 1 |
| NCT02497391 | Completed Has Results | Drug: Evacetrapib | Healthy | Eli Lilly and Company | July 2015 | Phase 1 |
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