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Navafenterol (AZD-8871) is a novel and potent inhaled long-acting dual-pharmacology muscarinic antagonist/β 2 -adrenoceptor agonist (MABA) in development for the treatment of obstructive airways diseases. The safety, tolerability, pharmacodynamics, and pharmacokinetics of navafenterol were investigated in patients with mild asthma.
Physicochemical Properties
| Molecular Formula | C38H42N6O6S2 |
| Exact Mass | 742.26 |
| CAS # | 1435519-06-4 |
| Related CAS # | Navafenterol saccharinate;1648550-37-1 |
| PubChem CID | 71558565 |
| Appearance | Typically exists as solid at room temperature |
| LogP | 3.9 |
| Hydrogen Bond Donor Count | 5 |
| Hydrogen Bond Acceptor Count | 12 |
| Rotatable Bond Count | 15 |
| Heavy Atom Count | 52 |
| Complexity | 1230 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | CN(CCCN1C2=C(C=C(C=C2)CNC[C@@H](C3=C4C=CC(=O)NC4=C(C=C3)O)O)N=N1)C5CCC(CC5)OC(=O)C(C6=CC=CS6)(C7=CC=CS7)O |
| InChi Key | ZNKWRAKPQQZLNX-ZDQHWEPJSA-N |
| InChi Code | InChI=1S/C38H42N6O6S2/c1-43(25-8-10-26(11-9-25)50-37(48)38(49,33-5-2-19-51-33)34-6-3-20-52-34)17-4-18-44-30-14-7-24(21-29(30)41-42-44)22-39-23-32(46)27-12-15-31(45)36-28(27)13-16-35(47)40-36/h2-3,5-7,12-16,19-21,25-26,32,39,45-46,49H,4,8-11,17-18,22-23H2,1H3,(H,40,47)/t25-,26-,32-/m0/s1 |
| Chemical Name | (1r,4r)-4-((3-(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-1H-benzo[d][1,2,3]triazol-1-yl)propyl)(methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiophen-2-yl)acetate |
| Synonyms | AZD-8871 AZD 8871 AZD8871 LAS-191351 LAS 191351 LAS191351 |
| 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) |
Biological Activity
| ln Vitro | Navafenterol (AZD-8871) has pIC50 values of 9.9, 9.9, 9.5, 10.4, and 8.8 for human M1, M2, M3, M4, and M5 receptors, respectively[1]. Navafenterol's pEC50 values for β1, β2, and β3 adrenergic receptors are 9.0, 9.5, and 8.7, in that order. Compared to β1 and β3 subtypes (three-fold and six-fold, respectively), it is more selective for β2 adrenergic receptors [1]. When compared to M2 receptors, navafenterol shows kinetic selectivity for M3 receptors (half-life: 4.97 hours) (half-life: 0.46 hours) [1]. In isolated guinea pig tissues, navafenterol demonstrated dual antimuscarinic and β2-adrenoceptor functional activity (pIC50 in electrically stimulated trachea: 8.6; pEC50 in self-sounding isolated trachea: 8.8) and over time. There is still a transition[1]. |
| ln Vivo | In dogs and guinea pigs, navafenterol (AZD-8871) inhibits acetylcholine-induced bronchoconstriction and, at doses with bronchoprotective efficacy, has negligible effects on heart rate and salivation. Moreover, dogs who received AZD8871 had long-lasting benefits, with a bronchial protective half-life of more than 24 hours. With an ID40 of 0.40 µg/kg, navafenterol demonstrated dose-proportionate bronchial protection without a discernible potency difference [1]. |
| Animal Protocol |
Animal/Disease Models: Male Dunkin Hartley guinea pig (body weight 340-600 g) bronchoconstriction model [1] Doses: 10, 30, 100 and 300 μg/mL Route of Administration: Aerosol administration Experimental Results: Concentration-response inhibition of bronchoconstriction, The IC50 value is 2.1 µg/mL. Exhibits anti-sialic acid effects, with a maximum inhibition rate of 65% ± 11% on salivation at a concentration of 300 µg/mL, with an estimated IC50 of 138.4 µg/mL. Animal/Disease Models: Male anesthetized beagle dog [1] Doses: 0.3, 1, 3 or 10 µg/kg Route of Administration: Administered as a nebulized liquid aerosol; administration volume 3 mL Experimental Results: At all doses tested (0.3-10 µg/kg) demonstrated significant effects within 24 hrs (hrs (hours)). The dose of 10 µg/kg demonstrated long-lasting effects, with bronchial protection of 79% ± 3.6% at 24 hrs (hrs (hours)) and a calculated half-life longer than 24 hrs (hrs (hours)). |
| References | [1]. Mònica Aparici, et al. Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M3 Receptor Antagonist/ β 2-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile. J Pharmacol Exp Ther. 2019 Jul;370(1):127-136. |
Solubility Data
| 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 (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). 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). 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.) |