| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 50mg | |||
| Other Sizes |
| Targets |
LY-377604 targets adrenergic receptors with a mixed mechanism of action. It acts as a potent agonist at the human β3-adrenoceptor with an EC50 of 2.4 nM. Simultaneously, it functions as an antagonist at β1- and β2-adrenoceptors. This dual pharmacological profile is designed to selectively activate the β3-adrenoceptor, which is primarily expressed in adipose tissue and is involved in lipolysis and thermogenesis, while blocking β1- and β2-adrenoceptors, which are predominantly found in the heart and other tissues and are associated with unwanted cardiovascular effects. By activating β3-adrenoceptors, LY-377604 increases cAMP levels, leading to increased energy expenditure and fat oxidation.
|
|---|---|
| ln Vitro |
LY377604 is a β1- and β2-adrenergic receptor antagonist as well as a human β3-adrenergic receptor agonist with an EC50 of 2.4 nM. Cyclic adenosine monophosphate (cAMP) levels in CHO cells transfected with human β1-adrenergic or human β2-adrenergic receptors are maximally increased by LY377604, but cAMP accumulation is not stimulated [1].
In vitro studies have shown that LY-377604 is a potent agonist at the human β3-adrenergic receptor. It causes a maximal increase in cyclic adenosine monophosphate (cAMP) levels with an EC50 of 2.4 nM. This indicates that LY-377604 is highly potent in activating β3-adrenoceptor-mediated signaling pathways. As a β1- and β2-adrenoceptor antagonist, it blocks the effects of endogenous catecholamines at these receptor subtypes. This mixed profile is intended to provide the metabolic benefits of β3-adrenoceptor activation (increased energy expenditure and fat oxidation) while minimizing the cardiovascular side effects associated with β1- and β2-adrenoceptor stimulation. |
| ln Vivo |
Lipid consumption is stimulated when male Long-Evans rats fed a high-calorie diet are given LY377604. In rats treated with vehicles, this is the respiratory quotient that is observed to decline and lasts for around 4 hours before recovering to recorded values [1].
In vivo studies in rodent models have demonstrated that LY-377604 is effective in increasing energy expenditure and promoting fat oxidation. In diet-induced obese male Long-Evans rats, oral administration of LY-377604 at 10 mg/kg increased energy expenditure. The compound also reduced hyperglycaemia and induced lean body mass-sparing weight loss. These findings support the potential of LY-377604 as an antiobesity and antidiabetic agent. A Phase II study was conducted in the US in obesity, indicating that the compound progressed into clinical development. However, the current status of its development is not specified. |
| Enzyme Assay |
The in vitro receptor binding and functional assays for LY-377604 are designed to characterize its activity at adrenergic receptor subtypes. Receptor binding assays would typically involve competition binding studies using radiolabeled ligands specific for β1, β2, and β3 adrenoceptors expressed in cell membranes. Functional assays measure the compound's ability to modulate downstream signaling. For β3-adrenoceptor agonism, the most common assay is the measurement of cAMP accumulation in cells expressing the human β3-adrenoceptor. Cells are treated with varying concentrations of LY-377604, and the amount of cAMP produced is quantified using a competitive immunoassay. The EC50 for cAMP accumulation is 2.4 nM. For antagonism at β1- and β2-adrenoceptors, the compound's ability to inhibit agonist-induced cAMP accumulation is measured. These assays confirm LY-377604's mixed pharmacological profile.
|
| Cell Assay |
In vitro cell-based assays for LY-377604 are used to study its effects on adrenergic receptor signaling in relevant cell types. For β3-adrenoceptor agonism, cells expressing the human β3-adrenoceptor (e.g., CHO or HEK293 cells) are treated with LY-377604, and the accumulation of cAMP is measured as a readout of receptor activation. The EC50 for cAMP accumulation is 2.4 nM. For β1- and β2-adrenoceptor antagonism, cells expressing these receptors are stimulated with a known agonist (e.g., isoproterenol) in the presence or absence of LY-377604, and the inhibition of cAMP accumulation is measured. These assays confirm the compound's dual mechanism of action. Additionally, adipocyte cell lines can be used to study the effects of LY-377604 on lipolysis and other metabolic endpoints.
|
| Animal Protocol |
In vivo animal experiments for LY-377604 have been conducted in rodent models of obesity and diabetes. In a typical study, diet-induced obese male Long-Evans rats are administered LY-377604 orally at a dose of 10 mg/kg. Energy expenditure is measured using indirect calorimetry, which assesses oxygen consumption and carbon dioxide production. Fat oxidation is calculated from the respiratory exchange ratio. Body weight, food intake, and glucose levels are also monitored. The compound's effects are compared to a vehicle control group. These studies have demonstrated that LY-377604 increases energy expenditure, promotes fat oxidation, reduces hyperglycaemia, and induces lean body mass-sparing weight loss. The compound's efficacy in these models supported its progression to a Phase II clinical study for obesity.
|
| ADME/Pharmacokinetics |
LY-377604 has a molecular weight of 524.6 g/mol and a molecular formula of C31H32N4O4. For research use, it is typically supplied as a solid and is soluble in DMSO at 80 mg/mL (152.49 mM). For in vivo administration, a common formulation includes 10% DMSO, 40% PEG300, 5% Tween 80, and 45% saline. The compound is stable as a powder at -20°C for up to 3 years and in solvent at -80°C for up to 1 year. The density is predicted to be 1.282 g/cm³. Pharmacokinetic properties such as half-life, bioavailability, and tissue distribution have not been detailed in the available literature.
|
| Toxicity/Toxicokinetics |
Detailed toxicity data for LY-377604 is not provided in standard product descriptions. As a research compound that progressed to Phase II clinical studies, its safety profile would have been evaluated in preclinical toxicology studies. However, specific toxicity data, such as LD50, organ toxicity, or genotoxicity, are not available. In vitro studies have shown that the compound is a potent agonist at the β3-adrenoceptor and antagonist at β1- and β2-adrenoceptors. The safety of the compound would depend on its selectivity and the physiological roles of the target receptors. As with all research chemicals, standard laboratory safety precautions should be followed when handling LY-377604.
|
| References | |
| Additional Infomation |
Ly377604 has been used in trials for the treatment of obesity.
LY-377604 is a research compound that has been investigated as a potential antidiabetic and antiobesity agent. It is a novel mixed β3-adrenoceptor agonist and β1- and β2-adrenoceptor antagonist. Its mechanism of action involves activating β3-adrenoceptors to increase energy expenditure and fat oxidation while blocking β1- and β2-adrenoceptors to minimize cardiovascular side effects. In rodent models, LY-377604 increased energy expenditure, fat oxidation, reduced hyperglycaemia, and induced lean body mass-sparing weight loss. A Phase II study was conducted in the US in obesity, indicating that the compound progressed into clinical development. LY-377604 is a valuable tool for studying the role of β3-adrenoceptors in metabolism and for exploring the therapeutic potential of mixed adrenergic receptor modulators. |
| Molecular Formula |
C31H32N4O4
|
|---|---|
| Molecular Weight |
524.62
|
| Exact Mass |
524.242
|
| CAS # |
204592-94-9
|
| PubChem CID |
9849699
|
| Appearance |
Off-white to light brown solid powder
|
| LogP |
6.233
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
11
|
| Heavy Atom Count |
39
|
| Complexity |
789
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CC(C)(CC1=CC=C(C=C1)OC2=NC=C(C=C2)C(=O)N)NC[C@@H](COC3=CC=CC4=C3C5=CC=CC=C5N4)O
|
| InChi Key |
RBSGUQYXRDKPAE-QFIPXVFZSA-N
|
| InChi Code |
InChI=1S/C31H32N4O4/c1-31(2,16-20-10-13-23(14-11-20)39-28-15-12-21(17-33-28)30(32)37)34-18-22(36)19-38-27-9-5-8-26-29(27)24-6-3-4-7-25(24)35-26/h3-15,17,22,34-36H,16,18-19H2,1-2H3,(H2,32,37)/t22-/m0/s1
|
| Chemical Name |
6-[4-[2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide
|
| Synonyms |
LY-377604 LY377604 LY 377604
|
| 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 (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
|
|---|---|
| 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 | 1.9061 mL | 9.5307 mL | 19.0614 mL | |
| 5 mM | 0.3812 mL | 1.9061 mL | 3.8123 mL | |
| 10 mM | 0.1906 mL | 0.9531 mL | 1.9061 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 |
| NCT00993421 | TERMINATEDWITH RESULTS | Drug: LY377604 Drug: Sibutramine Drug: Metoprolol Drug: Placebo sibutramine Drug: Placebo Metoprolol Drug: Placebo LY377604 |
Obesity | Eli Lilly and Company | 2009-10 | Phase 2 |
|
|
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
