YM17E is an inhibitor of acyl CoA:cholesterol acyltransferase (ACAT). The IC₅₀ value for inhibiting ACAT activity in rabbit liver microsomes in vitro is 4.4 × 10⁻⁸ M. [1]
YM17E is a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). It non-competitively inhibits microsomal ACAT from rabbit liver (IC₅₀ = 45 nM) and intestine (IC₅₀ = 34 nM), with a Kᵢ value of 86 nM (for liver microsomes). [2]

YM17E is as efficient in suppressing ACAT activity in the liver as it is in the gut, with IC50 values of 45 and 34 nM, respectively [2].

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YM17E inhibited the production of cholesteryl oleate from [¹⁴C]oleoyl CoA in a dose-dependent manner in both rabbit liver and intestinal microsomes. [2]

In a dose-dependent manner, YM17E (3, 10, and 30 mg/kg daily, orally) lowers non-HDL cholesterol, cholesteryl esters, and total cholesterol. The liver's levels of total cholesterol and cholesterol ester did not considerably decrease following an intravenous injection of YM17E, but they did significantly decrease following oral administration of the drug in a dose-dependent manner. Hepatic ACAT activity was dramatically reduced by YM17E (3, 5, 10 mg/kg, iv) in a dose-dependent manner. When given orally and intravenously, YM17E dramatically raises the clearance of 125I-LDL in rats fed an atherogenic diet [1]. YM17E, when employed as an enzyme source in liver and intestine microsomes, inhibits the synthesis of [14C]oleoyl-CoA to [14C]cholesterol oleate in a dose-dependent manner [2].

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In cholesterol-fed rats, oral administration of YM17E (3, 10, 30 mg/kg/day for 5 days) dose-dependently decreased serum total cholesterol, cholesteryl ester, and non-HDL cholesterol levels, while HDL cholesterol tended to increase. [1]
In cholesterol-fed rats, intravenous administration of YM17E (3, 5, 10 mg/kg/day for 5 days) also decreased serum total cholesterol, cholesteryl ester, and non-HDL cholesterol levels. The effect appeared to plateau at 5 mg/kg/day. HDL cholesterol increased. [1]
Oral administration of YM17E (10 mg/kg/day for 5 days) significantly inhibited gastrointestinal absorption of cholesterol (absorption ratio decreased from 82.2% in controls to 50.1%). Intravenous administration at the same dose did not significantly inhibit cholesterol absorption. [1]
Intravenous administration of YM17E (5 mg/kg/day for 5 days) significantly and dose-dependently inhibited hepatic ACAT activity in cholesterol-fed rats. [1]
In Triton WR-1339 treated rats (which elevates VLDL secretion), intravenous pretreatment with YM17E (10 mg/kg/day for 4 days) significantly suppressed the increase in serum cholesteryl ester levels, suggesting inhibition of VLDL/cholesteryl ester secretion from the liver. [1]
In cholesterol-fed rats, both oral (10 mg/kg/day) and intravenous (5 mg/kg/day) administration of YM17E for 5 days significantly increased the plasma clearance rate of ¹²⁵I-LDL, suggesting a decrease in LDL production. [1]
The hypocholesterolemic effect after oral administration at low plasma concentrations is primarily due to inhibition of intestinal cholesterol absorption. When plasma concentrations reach higher levels (as achieved by intravenous administration or high oral doses), hepatic ACAT inhibition also contributes significantly to the cholesterol-lowering effect. [1]
In normal chow-fed rats, oral administration of YM17E (10 and 30 mg/kg/day for 5 days) significantly decreased serum non-HDL cholesterol levels. The highest dose (30 mg/kg) also significantly decreased non-esterified fatty acids. [2]
In atherogenic diet-fed rats, oral administration of YM17E (3, 10, 30 mg/kg/day for 5 days) dose-dependently and markedly decreased serum total cholesterol, non-HDL cholesterol, free cholesterol, cholesteryl ester, phospholipids, and non-esterified fatty acids, while increasing HDL cholesterol. The ED₅₀ for reducing serum total cholesterol was 8 mg/kg. [2]
Ex vivo measurement showed that oral administration of YM17E (30 mg/kg/day for 5 days) to atherogenic diet-fed rats strongly inhibited hepatic ACAT activity (96% inhibition) and partially inhibited intestinal ACAT activity (53% inhibition). [2]
In cholesterol-fed rats, a single oral dose of YM17E (30 mg/kg) significantly inhibited the appearance of orally administered [³H]cholesterol in the serum over 4-8 hours, indicating inhibition of cholesterol absorption from the gut. [2]
In cholesterol-fed rats, oral administration of YM17E (10, 30, 100 mg/kg) dose-dependently increased the biliary excretion of neutral sterols derived from intravenously administered [¹⁴C]cholesterol. Conversion of cholesterol into bile acids was also increased at higher doses (30, 100 mg/kg). [2]
In cholesterol-fed beagle dogs, oral administration of YM17E at a total daily dose of 30 mg/kg significantly lowered serum total cholesterol. When the same total daily dose was divided into 5 administrations per day (6 mg/kg x 5), the cholesterol-lowering effect was significantly stronger (60% decrease vs 45% decrease with single 30 mg/kg dose) and the incidence of diarrhea was significantly reduced. [2]
YM17E caused secretory diarrhea with soft or mucous feces in beagle dogs. In a preliminary study, the frequency of diarrhea increased at doses of 15 mg/kg and higher. Diarrhea was also observed after subcutaneous administration (50 mg/kg) in normal chow-fed dogs. The effects were transient and reversible upon cessation of dosing. [2]

ACAT activity in liver microsomes was determined. Liver microsomes were prepared from rat liver. The assay measured the enzymatic synthesis of cholesteryl oleate from cholesterol and oleoyl CoA. Radiolabeled [¹⁴C]oleoyl CoA was used as a substrate. The lipids in the reaction mixture were separated by thin-layer chromatography. The radioactivity in the synthesized cholesteryl oleate band was quantified using an imaging analyzer. [1]
ACAT enzyme activity was assayed using microsomes prepared from rabbit liver or intestine. The assay mixture contained diluted microsomes, bovine serum albumin, cholesterol-containing liposomes, the test drug (in DMSO), and phosphate buffer. After pre-incubation, [¹⁴C]oleoyl CoA was added to start the reaction. The reaction was terminated by adding a chloroform:methanol mixture. Lipids were extracted, separated by thin-layer chromatography, and the band corresponding to enzymatically synthesized cholesteryl [¹⁴C]oleate was excised. The radioactivity in this band was quantified by liquid scintillation counting to determine ACAT activity. [2]

For in vivo efficacy studies, male SD rats (150-200 g) were fed an atherogenic diet (supplemented with 1.5% cholesterol, 0.5% cholic acid, 10% coconut oil) for 3 days before and during drug treatment. YM17E was administered for 5 consecutive days. For intravenous administration, it was dissolved in isotonic saline containing 20 mM phosphoric acid and injected via the tail vein. For oral administration, it was suspended in 0.5% methyl cellulose and given by gavage. Doses ranged from 3 to 30 mg/kg/day. Blood and tissues were collected at designated times (e.g., 2 hours after the last dose) for analysis. [1]
For the cholesterol absorption study using the double isotope method, rats were dosed with YM17E or vehicle for 5 days. Immediately after the last dose, they received [¹⁴C]cholesterol orally and [³H]cholesterol intravenously. Blood was collected 48 hours later to calculate the cholesterol absorption ratio. [1]
For the Triton WR-1339 study, rats were pretreated intravenously with YM17E or vehicle for 4 days. On the final day, Triton WR-1339 (270 mg/kg) was injected intravenously. Blood was collected 2 hours later to measure serum cholesterol. [1]
For the ¹²⁵I-LDL clearance study, rats were treated with YM17E or vehicle for 5 days. They then received an intravenous injection of ¹²⁵I-labeled LDL. Blood samples were collected at multiple time points afterward to measure serum radioactivity and calculate LDL clearance. [1]
For rat studies, male SD rats were fed normal chow, an atherogenic diet (CE-2 supplemented with 1.5% cholesterol, 0.5% cholic acid, 10% coconut oil), or a cholesterol-enriched diet (CE-2 + 1% cholesterol). YM17E or vehicle (0.5% methylcellulose) was administered orally by gavage once daily for 5 days. Blood and tissues were collected 2 hours after the last dose for analysis. [2]
For the bile excretion study in cholesterol-fed rats, animals were pretreated orally with YM17E for 5 days. On the surgery day, after the last dose, rats were anesthetized, and a bile duct cannula was inserted. Bile was collected after intravenous injection of [¹⁴C]cholesterol. [2]
For the cholesterol absorption study in cholesterol-fed rats, animals received a single oral dose of YM17E (30 mg/kg) or vehicle, immediately followed by oral administration of [³H]cholesterol. Blood samples were collected at various time points over 72 hours. [2]
For the beagle dog diarrhea study, male beagle dogs were fed an atherogenic diet multiple times daily. After one week, dogs received YM17E orally in capsules for 2 weeks. One group received a single 30 mg/kg dose daily, while another received the same total daily dose (30 mg/kg) divided into five 6 mg/kg doses administered after each feeding. Control dogs received lactose capsules. Blood was collected on days 0, 7, and 14 for lipid analysis and on day 14 for drug concentration measurement. [2]

Following oral administration of YM17E (10 mg/kg/day) to cholesterol-fed rats for 5 consecutive days, YM17E and its five active metabolites (M1, M2a, M2b, M3, M4) were distributed in tissues. Inhibitor concentrations (total concentrations of parent drug and metabolites, adjusted for potency) were very high in the small intestinal mucosa (approximately 400 times higher than plasma concentrations) and also high in the liver (approximately 40 times higher than plasma concentrations). [1] After intravenous administration of YM17E for 5 consecutive days, inhibitor concentrations in plasma and intestinal mucosa were similar, while the concentration in the liver was still approximately 40 times higher than plasma concentrations. [1] Within the tested dose range, the pharmacokinetic properties of YM17E administered orally and intravenously were linear. [1]
YM17E is metabolized into five active metabolites (M1, M2a, M2b, M3, and M4), which together exert pharmacological activity. [1]
In the beagle dog study, the plasma concentration of unmetabolized YM17E was measured on the last day of administration. For the fractionated dosing regimen (6 mg/kg five times daily), the area under the curve (AUC) was 1708 ± 276 ng·h/ml, and the maximum concentration (Cmax) was 160 ± 26 ng/ml. For the once-daily dosing regimen (30 mg/kg once daily), the AUC was 1371 ± 163 ng·h/ml, and the Cmax was 236 ± 30 ng/ml. [2]

The main toxicity of YM17E observed in beagles was secretory diarrhea, occurring at doses close to those producing a cholesterol-lowering effect (15 mg/kg and above). [2] In rats, oral administration of 50 mg/kg of YM17E daily for 13 weeks did not cause adrenal degeneration or necrosis, but reduced intracellular lipid vacuoles in the zona fasciculata. [2]

[1]. Relationship between bioavailability and hypocholesterolemic activity of YM17E, an inhibitor of ACAT, in cholesterol-fed rats. Atherosclerosis. 1998 Mar;137(1):97-106.

[2]. Pharmacological properties of YM17E, an acyl-CoA:cholesterol acyltransferase inhibitor, and diarrheal effect in beagle dogs. Jpn J Pharmacol. 1997 Jan;73(1):41-50.

YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)ureo]methyl]phenyl dihydrochloride) is a phenyl diurea derivative and belongs to the ACAT inhibitors. [1]
The cholesterol-lowering mechanism of YM17E depends on its bioavailability and the resulting plasma/tissue concentration. At low systemic exposure, it mainly works by inhibiting intestinal ACAT and cholesterol absorption. At high systemic exposure (achieved through high oral bioavailability or intravenous administration), it also inhibits hepatic ACAT, thereby reducing VLDL/LDL production and secretion. [1]
A clinical study cited in the literature showed that oral administration of YM17E (300 mg twice daily) for one week in healthy male volunteers reduced serum cholesterol levels. [1]
YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)ureo]methyl]phenyl dihydrochloride) is a novel ACAT inhibitor. [2]
Its cholesterol-lowering activity in cholesterol-fed rats stems from a dual effect of inhibiting intestinal cholesterol absorption and promoting cholesterol excretion from the liver into bile. [2]
The diarrhea observed in dogs may be related to the disruption of normal intestinal lipid absorption caused by ACAT inhibition and/or increased bile acid excretion. Divided administration to reduce peak plasma concentration (Cmax) reduces the incidence of diarrhea without affecting or even enhancing the cholesterol-lowering effect. [2]
Diarrhea occurred in dogs and humans at doses that lower serum cholesterol, but was not observed in rats, hamsters, or rabbits. [2]

C40H56N6O2

652.911649703979

652.446

124900-72-7

180289

White to off-white solid powder

1.2±0.1 g/cm3

862.7±65.0 °C at 760 mmHg

475.5±34.3 °C

0.0±3.3 mmHg at 25°C

1.620

8.77

2

4

10

48

869

0

LZQSLXDZJBXHRS-UHFFFAOYSA-N

InChI=1S/C40H56N6O2/c1-43(2)35-24-20-33(21-25-35)41-39(47)45(37-16-9-5-6-10-17-37)29-31-14-13-15-32(28-31)30-46(38-18-11-7-8-12-19-38)40(48)42-34-22-26-36(27-23-34)44(3)4/h13-15,20-28,37-38H,5-12,16-19,29-30H2,1-4H3,(H,41,47)(H,42,48)

1-cycloheptyl-1-[[3-[[cycloheptyl-[[4-(dimethylamino)phenyl]carbamoyl]amino]methyl]phenyl]methyl]-3-[4-(dimethylamino)phenyl]urea

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 : ≥ 125 mg/mL (~191.45 mM)

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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