Alvimopan

Alias: LY246736; LY246736; LY-246736; HSDB 7704; HSDB7704; HSDB-7704; ADL 8-2698; ADL8-2698; ADL-8-2698; Alvimopan; Brand name Entereg

Cat No.:V3722 Purity: ≥98%

COA Product Data Instructions for use SDS

Alvimopan Chemical Structure CAS No.: 156053-89-3
Product category: Opioid Receptor

This product is for research use only, not for human use. We do not sell to patients.

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Top Publications Citing lnvivochem Products

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

Science Adv 2022: 8, eabm9427.

Nature 597, 119–125 (2021)

Cell Stem Cell 2020,26(6):845-861.e12.

Science Trans Med 2023,15(701):eadd7872.

STTT 2023,8(1):91.

Cell Reports 2023,42(4):112313

Science Trans Med 2023, 15: eadd7872.

Cancer Cell 2021,39(4):529-547.e7.

Cancer Discov 2022,12(4):1106-1127.

Immunity 2023,56(3):620-634.e11.

J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

Biomaterial 2023 Sep16:302:122333.

Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

COA

MSDS

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Clinical Trial Information
Biological Data

Product Description

Alvimopan (also known as ADL 8-2698; LY 246736; HSDB-7704) is a novel peripheral micro opioid antagonist in clinical development for the management of post-operative ileus and opioid-induced bowel dysfunction. Alvimopan acts for a longer period of time than other antagonists that act more quickly, which may be connected to a slower rate of dissociation from the micro opioid receptor. In comparison to the long-acting partial agonist buprenorphine (t(1/2)=44 min), alvimopan's dissociation rate from the micro opioid receptor (t(1/2)=30–44 min) was slower than that of the antagonists naloxone (t(1/2)=0.82 min) and N-methylnaltrexone (t(1/2)=0.46 min). Moreover, after preincubation with the micro opioid receptor, increases were seen in the apparent affinities and potencies of buprenorphine and alvimopan, but not of naloxone or methylnaltrexone. Alvimopan does not dissociate from the micro opioid receptor as quickly as other drugs that act more quickly, which is consistent with its prolonged duration of action.

Biological Activity I Assay Protocols (From Reference)

Targets

μ-opioid receptor ( Ki = 0.77 nM ); δ-opioid receptor ( IC50 = 4.4 nM ); δ-opioid receptor ( Ki = 4.4 nM ); κ-opioid receptor ( Ki = 40 nM )

ln Vitro

In vitro activity: Alvimopan has a more modest (≥6-fold) μ/δ receptor selectivity, but is highly selective (by ≥227-fold) for the human μ receptor over the κ subtype. Alvimopan has pA2 values of 9.6 or 9.7 and is a strong antagonist of morphine, DAMGO or endomorphin-1-induced, and μ opioid receptor-mediated electrically evoked contraction inhibition in the isolated ileum of guinea pigs. The ileum of guinea pigs has lower alvimopan antagonist potencies (δ and κ antagonists, with pA2 values of 8.7 and 7.8, respectively). Upon testing at various non-opioid receptors, ion channels, and enzymes, alvimopan (1 or 10 μM) does not exhibit any noteworthy affinity[2].

ln Vivo

Alvimopan only counteracts morphine-induced analgesia in animals at relatively high dosages; in order for the drug to cross the blood-brain barrier, very high plasma concentrations are required. Alvimopan is about 200 times more effective at blocking peripheral than central μ-receptors after intravenous injection. Alvimopan is also very active when taken orally. Alvimopan administered intravenously to dogs increased plasma area under the concentration-time curve and peak plasma concentrations in a dose-dependent manner. Oral doses up to 100 mg/kg, however, resulted in low plasma concentrations (mean C_max = 92.9 ng/ml) due to poor systemic absorption, which led to an oral bioavailability of about 0.03%. In dogs and rabbits, the half-life of alvimopan is thought to be roughly 10 minutes following intravenous administration[1].

Enzyme Assay

Alvimopan has a more modest (≥6-fold) μ/δ receptor selectivity, but is highly selective (by ≥227-fold) for the human μ receptor over the κ subtype. Alvimopan has pA2 values of 9.6 or 9.7 and is a strong antagonist of morphine, DAMGO or endomorphin-1-induced, and μ opioid receptor-mediated electrically evoked contraction inhibition in the isolated ileum of guinea pigs. The ileum of guinea pigs has lower alvimopan antagonist potencies (δ and κ antagonists, with pA2 values of 8.7 and 7.8, respectively). Tested at both 1 and 10 μM, alvimopan does not exhibit any noteworthy affinity for a wide variety of non-opioid receptors, ion channels, or enzymes.

Animal Protocol

100 mg/kg; i.v.

dogs and rabbits

References

[1]. P T. 2008 Oct; 33(10): 574, 580-583.

[2]. Therapeutics. 2009, 1: 199-213.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C25H32N2O4
Molecular Weight	424.54
Exact Mass	424.24
Elemental Analysis	C, 70.73; H, 7.60; N, 6.60; O, 15.07
CAS #	156053-89-3
Related CAS #	Alvimopan dihydrate; 170098-38-1; Alvimopan monohydrate; 1383577-62-5
Appearance	Solid powder
SMILES	O=C(O)CNC([C@H](CN1C[C@H](C)[C@](C)(C2=CC=CC(O)=C2)CC1)CC3=CC=CC=C3)=O
InChi Key	UPNUIXSCZBYVBB-JVFUWBCBSA-N
InChi Code	InChI=1S/C25H32N2O4/c1-18-16-27(12-11-25(18,2)21-9-6-10-22(28)14-21)17-20(24(31)26-15-23(29)30)13-19-7-4-3-5-8-19/h3-10,14,18,20,28H,11-13,15-17H2,1-2H3,(H,26,31)(H,29,30)/t18-,20-,25+/m0/s1
Chemical Name	((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propanoyl)glycine
Synonyms	LY246736; LY246736; LY-246736; HSDB 7704; HSDB7704; HSDB-7704; ADL 8-2698; ADL8-2698; ADL-8-2698; Alvimopan; Brand name Entereg
HS Tariff Code	2934.99.9001
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)

Solubility Data

Solubility (In Vitro)

DMSO: 85~92 mg/mL (200.2~199.8 mM)

Water: >1mg/mL

Ethanol: >1mg/mL

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
(e.g. IP/IV/IM/SC)

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)

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).

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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

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.

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

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.3555 mL	11.7775 mL	23.5549 mL
	5 mM	0.4711 mL	2.3555 mL	4.7110 mL
	10 mM	0.2355 mL	1.1777 mL	2.3555 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.

Calculator

Mass

Concentration

Volume

Molecular Weight*

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Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

Calculate the Mass of a compound required to prepare a solution of known volume and concentration
Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
Calculate the Concentration of a solution resulting from a known mass of compound in a specific volume

See Example

An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
Enter 10 in the Concentration box and choose the correct unit (mM)
Enter 5 in the Volume box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

Concentration (Start)

Volume (Start)

Concentration (End)

Volume (End)

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
Enter 25 into the Concentration (End) box and select the correct unit (mM)
Enter 25 into the Volume (End) box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

Total molecular weight

g/mol

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:

To calculate molar mass of a chemical compound, please enter the chemical/molecular formula and click the “Calculate’ button.

Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

Volume (to add to vial)

Mass (in vial)

Desired Reconstitution Concentration

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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
Click the “Calculate” button
The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

Dosage mg/kg

Average weight of animals g

Dosing volume per animal μL

Number of animals

Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

% DMSO

% Tween 80

% ddH₂O

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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.

Note： (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.

Clinical Trial Information

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT04405037	Recruiting	Drug: Alvimopan	Gastrointestinal Dysfunction Ileus	Scott Steele	August 1, 2020	Phase 4
NCT03216525	Completed	Drug: Alvimopan Drug: Placebo	Ileus Spinal Fusion	Washington University School of Medicine	August 2014	Not Applicable
NCT02218190	Completed	Drug: Alvimopan	Migraine	Ortho-McNeil Neurologics, Inc.	June 2004	Phase 4
NCT02789111	Completed	Drug: Alvimopan Drug: Placebo	Constipation	University of Virginia	June 1, 2016	Phase 4
NCT02742181	Completed	Drug: Alvimopan Other: Control Group	Colorectal Surgery Ileus	Sharon Stein	December 2, 2015	Phase 3

Biological Data

Chemical structure of alvimopan (Entereg). P T. 2008 Oct; 33(10): 574, 580-583.

The effects of subcutaneous alvimopan and ADL 08-0011 on morphine-induced slowing of small intestinal transit (assessed with respect to the distance travelled by an orally dosed charcoal meal) and analgesia (hot-plate assay) in mice (n = 6-9), and b) the doses associated with 50% reversal (ID50 values) of morphine-induced responses, with the derived peripheral selectivities for each compound. Therapeutics. 2009, 1: 199-213.

Hazard ratios (with 95% confidence intervals) for (a) GI-3 and (b) GI-2 recoveries in each of the Phase 3 studies performed with alvimopan (12 mg b.i.d.) in patients undergoing bowel resection. Therapeutics. 2009, 1: 199-213.

Proportion of patients with postoperative morbidity related to POI in each of the Phase 3 studies performed with alvimopan (12 mg b.i.d.) in patients undergoing bowel resection. Therapeutics. 2009, 1: 199-213.