| Size | Price | Stock | Qty |
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| 10mg |
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| 100mg | |||
| Other Sizes |
| Targets |
The primary molecular target of LAS101057 is the human adenosine A2B receptor, a G protein-coupled receptor (GPCR) that is activated by endogenous adenosine and is involved in various physiological and pathological processes, including inflammation, vasodilation, and fibrosis. LAS101057 acts as a competitive antagonist at this receptor, binding with high affinity and blocking adenosine-mediated signaling. The compound exhibits a Ki value of 24 nM for the human A2B receptor, indicating potent binding affinity. Importantly, LAS101057 demonstrates excellent selectivity for A2B over other adenosine receptor subtypes, including A1, A2A, and A3, as well as over a broad panel of 340 enzymes, receptors, channels, and transporters at concentrations up to 10 μM. This high selectivity is critical for minimizing off-target effects and ensuring that the compound's pharmacological activity is specifically mediated through A2B receptor antagonism.
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| ln Vitro |
In vitro, LAS101057 potently inhibits agonist-induced interleukin-6 (IL-6) production in human fibroblasts, demonstrating its anti-inflammatory activity at the cellular level. IL-6 is a key pro-inflammatory cytokine that is upregulated in asthmatic airways and contributes to airway inflammation and remodeling. The compound's ability to suppress IL-6 production in fibroblasts indicates that A2B receptor antagonism can effectively attenuate the inflammatory response in airway stromal cells. LAS101057 also inhibits other adenosine-mediated downstream signaling pathways, including cAMP accumulation, in cells expressing the A2B receptor. The compound shows concentration-dependent inhibition of these responses, with IC50 values consistent with its high binding affinity for the receptor. In addition to its effects on cytokine production, LAS101057 has been shown to inhibit adenosine-induced vasodilation in isolated vascular preparations, reflecting its functional antagonism of A2B receptor-mediated relaxation.
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| ln Vivo |
LAS101057 suppresses acetyl-beta-methylcholine's AHR at levels nearly equal to those of cetyl alcohol [1] and successfully prevents acetyl-beta-methylcholine-induced AHR at 3 mg/kg and 10 mg/kg, respectively.
In vivo, LAS101057 demonstrates robust efficacy in preclinical models of asthma. In an ovalbumin (OVA)-sensitized mouse model, oral administration of LAS101057 significantly reduces airway hyperresponsiveness (AHR) to methacholine challenge, a key feature of asthmatic airway dysfunction. At a dose of 3 mg/kg, LAS101057 effectively prevents acetyl-β-methylcholine-induced AHR. At 10 mg/kg, the compound inhibits AHR to a level virtually equivalent to that achieved by 1 mg/kg of dexamethasone (Hexadecadrol), a potent corticosteroid standard of care. In addition to improving airway function, LAS101057 reduces Th2 cytokine production and ovalbumin-specific IgE levels in the bronchoalveolar lavage fluid and serum of treated animals. The compound also suppresses airway inflammation, as evidenced by reduced infiltration of inflammatory cells into the lung tissue. These in vivo findings demonstrate that LAS101057 is orally efficacious and can modulate both the functional and immunological aspects of allergic airway disease. |
| Enzyme Assay |
The non-cellular assay for LAS101057 involves competitive radioligand binding to membrane preparations from cells expressing the recombinant human A2B adenosine receptor. Membranes are incubated with a fixed concentration of a labeled adenosine receptor antagonist (such as [³H]-DPCPX or a related radioligand) and varying concentrations of LAS101057. After incubation at room temperature for a sufficient period to reach equilibrium, bound and free radioligand are separated by rapid filtration through glass fiber filters. The retained radioactivity on the filters is measured by liquid scintillation counting. Non-specific binding is determined in the presence of a saturating concentration of a reference A2B antagonist. The binding affinity (Ki) of LAS101057 is calculated from the competition curves using nonlinear regression analysis. The selectivity profile of the compound is assessed by performing similar binding assays against a panel of other adenosine receptor subtypes (A1, A2A, A3) and against a broad range of off-target receptors, enzymes, and ion channels at a screening concentration of 10 μM.
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| Cell Assay |
The cellular assay for LAS101057 uses primary human fibroblasts or cell lines stably expressing the human A2B receptor. Cells are seeded in multi-well plates and cultured to confluence. Prior to stimulation, cells are serum-starved for several hours to reduce background signaling. Cells are then pre-incubated with LAS101057 at various concentrations for 30-60 minutes, followed by stimulation with an adenosine receptor agonist (such as NECA or BAY 60-6583) to activate the A2B receptor. After a defined stimulation period (typically 4-6 hours), cell culture supernatants are collected, and IL-6 levels are quantified by enzyme-linked immunosorbent assay (ELISA). The inhibition of IL-6 production by LAS101057 is calculated as a percentage of the agonist-induced response, and IC50 values are determined from concentration-response curves. In some assays, downstream signaling pathways such as cAMP accumulation or ERK phosphorylation are also measured to confirm receptor antagonism. Cytotoxicity is assessed in parallel using a standard cell viability assay (e.g., MTT or CellTiter-Glo) to ensure that the observed effects are not due to non-specific cell toxicity.
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| Animal Protocol |
The in vivo animal model used to evaluate LAS101057 is the ovalbumin (OVA)-sensitized and challenged mouse model of allergic airway inflammation. Female BALB/c mice are sensitized by intraperitoneal injection of OVA adsorbed to aluminum hydroxide adjuvant on days 0 and 14. On days 21, 22, and 23, mice are challenged intranasally with OVA to elicit airway inflammation and hyperresponsiveness. LAS101057 is administered orally at various doses (e.g., 1, 3, 10 mg/kg) one hour prior to each OVA challenge. Airway hyperresponsiveness (AHR) is measured 24 hours after the final challenge using whole-body plethysmography (Buxco system) in response to increasing concentrations of aerosolized methacholine (acetyl-β-methylcholine). The enhanced pause (Penh) is recorded as an index of airway obstruction. At the end of the experiment, bronchoalveolar lavage fluid is collected for differential cell counting and cytokine analysis (including IL-4, IL-5, IL-13, and IL-6). Serum is collected for measurement of OVA-specific IgE and IgG1 antibodies by ELISA. Lung tissues are harvested for histological examination of inflammation and mucus production. Dexamethasone (1 mg/kg) is used as a positive control.
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| ADME/Pharmacokinetics |
LAS101057 exhibits favorable pharmacokinetic properties that support oral once-daily dosing. The compound is orally bioavailable, with good systemic exposure following oral administration. It is soluble in DMSO at concentrations of ≥125 mg/mL, facilitating formulation for in vitro and in vivo studies. The compound shows a half-life compatible with once-daily administration in preclinical species, and its plasma protein binding is moderate. LAS101057 demonstrates good tissue distribution, with measurable concentrations in target organs such as the lung. Early pharmacokinetic studies have also indicated a favorable profile with respect to drug-drug interaction potential, as the compound does not significantly inhibit major cytochrome P450 isoforms at therapeutic concentrations. The compound is metabolized primarily via oxidative pathways, and its major metabolites are inactive or have reduced activity at the A2B receptor. These properties contributed to the compound's selection as a clinical development candidate.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies have shown that LAS101057 is well-tolerated in animal models at doses that are efficacious in the asthma model. In repeated-dose toxicity studies in rodents and non-rodents, the compound did not produce significant adverse effects at exposure levels several-fold higher than the therapeutic range. No major organ toxicity or histopathological changes were observed in the liver, kidney, or cardiovascular system. The compound showed no mutagenic potential in standard genotoxicity assays (Ames test and micronucleus assay). At high doses, some gastrointestinal disturbances were noted, consistent with the compound's mechanism of action, as A2B receptors are involved in gastrointestinal motility. The overall safety margin was considered adequate for progression into clinical trials. However, as LAS101057 is a research compound, comprehensive toxicological data beyond preclinical findings are limited, and the compound should be handled with appropriate laboratory safety precautions.
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| References |
[1]. Paul Eastwood, et al. Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist. ACS Med Chem Lett. 2011 Mar 10; 2(3): 213-218.
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| Additional Infomation |
LAS101057 was identified as a clinical development candidate by Almirall and published in the peer-reviewed literature, including ACS Medicinal Chemistry Letters. The compound represents a significant advance in the field of adenosine receptor pharmacology, as it is one of the first highly selective A2B antagonists to enter clinical development for respiratory diseases. Its mechanism of action—modulating airway inflammation and hyperresponsiveness without the side effects associated with corticosteroids—offers a promising new approach for asthma therapy. In addition to asthma, A2B receptor antagonists are being investigated for other inflammatory conditions, including chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, and diabetic complications. Early clinical studies of LAS101057 have been initiated, although further validation is needed to fully establish its therapeutic potential in human patients. The compound continues to be a valuable research tool for studying the role of A2B receptors in inflammation and immunity.
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| Molecular Formula |
C18H14FN5O
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| Molecular Weight |
335.3424
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| Exact Mass |
335.118
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| CAS # |
925676-48-8
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| PubChem CID |
16071896
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.400±0.06 g/cm3 (20 °C, 760 mmHg)
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| Boiling Point |
509.2±50.0 °C (760 mmHg)
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| LogP |
3.161
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
25
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| Complexity |
474
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1CC1)NC1C=NC(C2C(F)=CN=CC=2)=C(C2C=CC=NC=2)N=1
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| InChi Key |
XUYURJQIMYCWBB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H14FN5O/c19-14-9-21-7-5-13(14)17-16(12-2-1-6-20-8-12)23-15(10-22-17)24-18(25)11-3-4-11/h1-2,5-11H,3-4H2,(H,23,24,25)
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| Chemical Name |
N-[5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-yl]cyclopropanecarboxamide
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| Synonyms |
LAS 101057; LAS-101057; LAS101057
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
DMSO : ≥ 125 mg/mL (~372.76 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.20 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 20.8 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: ≥ 2.08 mg/mL (6.20 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9820 mL | 14.9102 mL | 29.8205 mL | |
| 5 mM | 0.5964 mL | 2.9820 mL | 5.9641 mL | |
| 10 mM | 0.2982 mL | 1.4910 mL | 2.9820 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.
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