| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| Other Sizes |
| Targets |
AZD5462 targets the relaxin family peptide receptor 1 (RXFP1), a G protein-coupled receptor (GPCR) that is the cognate receptor for the human hormone relaxin-2. It acts as a selective, allosteric agonist, meaning it binds to a site distinct from the natural ligand to modulate receptor function. By activating RXFP1, AZD5462 mimics the signaling of relaxin H2. RXFP1 is widely expressed in the heart, kidneys, and other tissues, and its activation is associated with anti-fibrotic, anti-inflammatory, and vasodilatory effects.
|
|---|---|
| ln Vitro |
AZD5462 (Example 1) exhibits stimulatory activity with an EC50 of 17 nM for cAMP production and 50 nM for cGMP production [1]. With a 4.3% unbound (free) rate, AZD5462 binds to human plasma proteins and exhibits stability with Clint values of 23 μL/min/mg (human louse microsomes), 4.8 μL/min/106 cells (human liver cells), and 11 µL/min/106 cells (rat hepatocytes) [1]. With an EC50 of 6.3 nM, AZD5462 increases ERK phosphorylation[1].
In vitro, AZD5462 demonstrates potent agonist activity at the human RXFP1 receptor. It induces cAMP mobilization in HEK293 cells expressing human RXFP1 with an EC50 of 15.85 nM. Other reported EC50 values for cAMP production are 17 nM and for cGMP production are 50 nM. Additionally, AZD5462 enhances the phosphorylation of ERK with an EC50 of 6.3 nM. It binds to human plasma proteins with a 4.3% unbound fraction. In cell-based assays, it activates a highly similar panel of downstream pathways as relaxin H2. |
| ln Vivo |
In vivo, AZD5462 has demonstrated therapeutic potential in preclinical models and clinical trials. In a cynomolgus monkey model of heart failure, 8 weeks of treatment with AZD5462 led to robust improvements in functional cardiac parameters, including left ventricular ejection fraction (LVEF), without changes in heart rate or mean arterial blood pressure. In rats, AZD5462 increases heart rate and mean arterial blood pressure (MABP). The compound has completed Phase I studies in healthy volunteers and is currently in Phase IIb trials for chronic heart failure.
|
| Enzyme Assay |
For in vitro receptor binding and functional assays, the activity of AZD5462 is typically assessed using cell lines, such as HEK293 cells, engineered to express the human RXFP1 receptor. Receptor activation is measured by quantifying the production of second messengers like cAMP or cGMP, or by assessing downstream signaling events such as ERK phosphorylation. The compound's binding affinity and allosteric modulation can be further characterized using techniques like surface plasmon resonance or radioligand binding assays to determine its interaction kinetics and binding site.
|
| Cell Assay |
For in vitro cell-based assays, cells expressing RXFP1 are cultured and treated with varying concentrations of AZD5462. The functional response is typically measured by detecting the accumulation of cAMP using a homogeneous time-resolved fluorescence (HTRF) or ELISA-based kit. For ERK phosphorylation studies, cells are lysed after treatment, and phosphorylated ERK levels are quantified using Western blotting or phospho-specific ELISA assays. These assays are used to determine the compound's potency (EC50) and efficacy in activating the RXFP1 signaling pathway.
|
| Animal Protocol |
For in vivo animal studies, the efficacy of AZD5462 was assessed in a translatable cynomolgus monkey heart failure model. In this model, animals were treated with AZD5462 for 8 weeks, and cardiac function was monitored by echocardiography to measure parameters like LVEF. In rats, the compound's hemodynamic effects, such as changes in heart rate and blood pressure, were measured. For pharmacokinetic and toxicokinetic studies, the compound is typically administered orally to rats and monkeys, with plasma concentrations measured over time to determine PK parameters.
|
| ADME/Pharmacokinetics |
AZD5462 is an orally bioavailable small molecule. It demonstrates stability in human liver microsomes with a Clint value of 23 μL/min/mg, in human hepatocytes (4.8 μL/min/10^6 cells), and in rat hepatocytes (11 μL/min/10^6 cells). It binds to human plasma proteins with a 4.3% unbound fraction. The compound is soluble in DMSO (up to 100-150 mg/mL) but has limited aqueous solubility. For in vivo administration, it can be formulated as a homogeneous suspension in CMC-Na or as a clear solution in mixtures of DMSO, PEG300, Tween 80, and saline.
|
| Toxicity/Toxicokinetics |
A comprehensive toxicology profile for AZD5462 has been established in preclinical studies. The compound was reported to be well tolerated in both rat and cynomolgus monkey toxicology studies. However, specific toxicity data, such as NOAEL (No Observed Adverse Effect Level) or target organ toxicities, are not detailed in the publicly available summaries. As an investigational drug, its safety is being further evaluated in ongoing clinical trials, which monitor for adverse events and tolerability in humans.
|
| References | |
| Additional Infomation |
AZD5462 (Pexerelgon) is an investigational, first-in-class, oral small-molecule allosteric agonist of RXFP1. It is being developed by AstraZeneca for the treatment of chronic heart failure. The compound has completed Phase I studies and is currently in a Phase IIb trial (LUMINARA, NCT06299826) to evaluate its efficacy on cardiac function in patients with chronic heart failure. It is also being studied in combination with dapagliflozin in patients with heart failure and moderate renal impairment. AZD5462 represents the first small molecule targeting relaxin biology to enter clinical trials.
|
| Molecular Formula |
C30H41FN2O6
|
|---|---|
| Molecular Weight |
544.654752492905
|
| Exact Mass |
544.294
|
| CAS # |
2787501-83-9
|
| PubChem CID |
163395232
|
| Appearance |
White to off-white solid powder
|
| LogP |
5.3
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
9
|
| Heavy Atom Count |
39
|
| Complexity |
932
|
| Defined Atom Stereocenter Count |
4
|
| SMILES |
CC1(CCC1)CNC(=O)[C@H]2[C@@H]3CC[C@@H](C3)[C@H]2NC(=O)C4=CC(=C(C=C4OC)F)OC5CCC(CC5)(C)C(=O)O
|
| InChi Key |
LYUYYIGCZIZIGF-SRHODNEWSA-N
|
| InChi Code |
InChI=1S/C30H41FN2O6/c1-29(9-4-10-29)16-32-27(35)24-17-5-6-18(13-17)25(24)33-26(34)20-14-23(21(31)15-22(20)38-3)39-19-7-11-30(2,12-8-19)28(36)37/h14-15,17-19,24-25H,4-13,16H2,1-3H3,(H,32,35)(H,33,34)(H,36,37)/t17-,18+,19?,24+,25-,30?/m1/s1
|
| Chemical Name |
4-[2-fluoro-4-methoxy-5-[[(1S,2R,3S,4R)-3-[(1-methylcyclobutyl)methylcarbamoyl]-2-bicyclo[2.2.1]heptanyl]carbamoyl]phenoxy]-1-methylcyclohexane-1-carboxylic acid
|
| 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 | 1.8360 mL | 9.1802 mL | 18.3604 mL | |
| 5 mM | 0.3672 mL | 1.8360 mL | 3.6721 mL | |
| 10 mM | 0.1836 mL | 0.9180 mL | 1.8360 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
