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Purity: ≥98%
AZD5423 is the first clinical candidate that displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, AZD7594 (also known as AZ13189620), which is a novel, potent selective nonsteroidal indazole ether-based glucocorticoid receptor modulators (SGRMs) with an IC50 of 0.9 nM. AZD-7594 is an inhaled selective glucocorticoid receptor (GCCR) modulator for the inhaled treatment of respiratory diseases. AZD7594 demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment. AZD-7594 is currently in phase II clinical trials by AstraZeneca for the treatment of mild to moderate asthma. It is also in phase I clinical trials for the treatment of chronic obstructive pulmonary disorder (COPD).
| Targets |
AZD5423 is >900-fold selective for other steroid hormone receptors and has significant affinity for the glucocorticoid receptor, with an IC50 of 0.9 nM in the radioligand human glucocorticoid receptor assay [1].
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| ln Vitro |
AZD5423 is >900-fold selective for other steroid hormone receptors and has significant affinity for the glucocorticoid receptor, with an IC50 of 0.9 nM in the radioligand human glucocorticoid receptor assay [1].
The current clinical study article does not contain detailed in vitro experimental results (e.g., cell-based assays, Western blot, PCR) for AZD5423. It references prior work indicating that AZD5423 appears to interact preferentially with certain cofactors (e.g., nuclear receptor-interacting protein 1, nuclear receptor coactivator 1, peroxisome proliferator-activated receptor γ, coactivator 1α), potentially leading to an altered gene expression profile. [2] |
| ln Vivo |
In a randomized, double-blind, crossover study involving subjects with mild allergic asthma, 7-day once-daily inhalation of AZD5423 (300 µg) significantly attenuated the allergen-induced late asthmatic response (LAR). The maximum percentage fall in FEV1 during the LAR was -8.4% (SEM 1.6) with AZD5423 300 µg and -8.7% (SEM 1.7) with 75 µg, compared to -13.7% (SEM 2.3) with placebo. [2]
AZD5423 (300 µg) significantly attenuated allergen-induced airway hyperresponsiveness (AHR) 24 hours post-challenge compared to placebo. The provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) improved significantly from Day 1 to Day 7 with the 300 µg dose. The 75 µg dose also showed a significant inhibitory effect on the allergen-induced fall in PC20 compared to placebo. [2] Both doses of AZD5423 (75 and 300 µg) significantly attenuated allergen-induced sputum eosinophilia. At 7 hours post-allergen, reductions were 61% and 63% for the 75 µg and 300 µg doses, respectively, compared to placebo. At 24 hours, reductions were 34% and 46%, respectively. The 300 µg dose also showed a significantly greater reduction in sputum eosinophils at 24 hours compared to active control budesonide. [2] AZD5423 had no significant effect on the early asthmatic response (EAR), other sputum inflammatory cells (neutrophils, lymphocytes), or circulating leukocytes. [2] |
| Animal Protocol |
The article references a previous rat model of pulmonary inflammation (Sephadex bead-induced, eosinophil-driven) where AZD5423 administered via dry-powder inhalation demonstrated a dose-dependent inhibition of lung inflammation. In the same model, thymic involution (decrease in thymus weight) was used to quantify systemic GR agonism. The ratio of systemic effect (ED25 for thymus involution) to anti-inflammatory potency (ED50 for lung edema) for AZD5423 was approximately fivefold improved compared to the reference inhaled corticosteroid budesonide. [2]
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| ADME/Pharmacokinetics |
The pharmacokinetic characteristics of inhaled AZD5423 are rapid pulmonary absorption and rapid overall clearance. No significant deviation from dose-proportional pharmacokinetics was observed, nor was any time-dependent pharmacokinetic observed. The accumulation ratio is low (≤1.5). [2] Clearance data indicate that AZD5423 is a drug with high hepatic extractability. [2] Due to the low oral bioavailability of AZD5423 (approximately 3%), its systemic bioavailability is mainly derived from pulmonary absorption. [2]
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| Toxicity/Toxicokinetics |
In a 7-day clinical study, AZD5423 (75 and 300 µg) was well tolerated. No deaths, serious adverse events (AEs), or discontinuation due to AEs occurred. The most common AEs were typical adverse events associated with inhalation therapy (e.g., headache, oropharyngeal pain). The incidence of AEs was lowest during the 300 µg treatment period. [2]
Compared to placebo, AZD5423 treatment did not significantly alter serum dehydroepiandrosterone sulfate or osteocalcin concentrations, indicating that AZD5423 had no acute effect on the hypothalamic-pituitary-adrenal (HPA) axis or bone turnover markers in this short-term study. [2] Due to the short duration of the study, the systemic effects of glucocorticoid receptor agonists could not be adequately assessed. [2] |
| References |
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| Additional Infomation |
AZD5423 has been used in research trials on basic science and treatment of asthma, bioavailability and AUC, and chronic obstructive pulmonary disease (COPD).
AZD5423 is an inhaled, potent, selective nonsteroidal glucocorticoid receptor modulator designed to provide the beneficial anti-inflammatory effects of conventional glucocorticoid receptor agonists while reducing systemic adverse reactions. [2] Compared to classical glucocorticoids, the differential binding pattern and cofactor interaction profile of AZD5423 may lead to alterations in gene expression profiles and potentially improve the therapeutic window. [2] This study validated the efficacy of nonsteroidal glucocorticoid receptor agonists in a human model of allergic asthma, showing that they reduced key features: delayed bronchoconstriction, airway hyperresponsiveness, and eosinophilic inflammation. [2] |
| Exact Mass |
487.151
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|---|---|
| CAS # |
1034148-04-3
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| PubChem CID |
24825740
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| Appearance |
White to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
573.8±50.0 °C at 760 mmHg
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| Flash Point |
300.8±30.1 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.574
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| LogP |
5.89
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
35
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| Complexity |
704
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@@H]([C@@H](C1=CC(=CC=C1)OC)OC2=CC3=C(C=C2)N(N=C3)C4=CC=C(C=C4)F)NC(=O)C(F)(F)F
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| InChi Key |
FCNQMDSJHADDFT-WNSKOXEYSA-N
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| InChi Code |
InChI=1S/C25H21F4N3O3/c1-15(31-24(33)25(27,28)29)23(16-4-3-5-20(12-16)34-2)35-21-10-11-22-17(13-21)14-30-32(22)19-8-6-18(26)7-9-19/h3-15,23H,1-2H3,(H,31,33)/t15-,23-/m0/s1
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| Chemical Name |
2,2,2-Trifluoro-N-((1R,2S)-1-((1-(4-fluorophenyl)-1H-indazol-5-yl)oxy)-1-(3-methoxyphenyl)-2-propanyl)acetamide
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| Synonyms |
AZD-5423; AZD 5423; AZD5423; UNII-641H0Q518W;
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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 |
| 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 : ~100 mg/mL (~205.15 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.27 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 (4.27 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.) |
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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