AZD5423 / AstraZeneca - LARVOL DELTA

Machine learning-aided search for ligands of P2Y6 and other P2Y receptors. (PubMed, Purinergic Signal) - "The hit compound ABBV-744, an experimental anticancer drug with a 6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine scaffold, had multifaceted interactions with the P2YR family: hP2Y6R inhibition in a non-surmountable fashion, suggesting that noncompetitive antagonism, and hP2Y1R enhancement, but not hP2Y14R binding inhibition. Other machine learning-selected compounds were either weak (experimental anti-asthmatic drug AZD5423 with a phenyl-1H-indazole scaffold) or inactive in inhibiting the hP2Y6R. Experimental drugs TAK-593 and GSK1070916 (100 µM) inhibited P2Y14R fluorescent binding by 50% and 38%, respectively, and all other compounds by < 20%. Thus, machine learning has led the way toward revealing previously unknown modulators of several P2YR subtypes that have varied effects."

Journal • Machine learning • Asthma • Astrocytoma • Brain Cancer • CNS Disorders • Immunology • Metabolic Disorders • Oncology • Respiratory Diseases • Solid Tumor

RIPK3 inhibitor-AZD5423 alleviates acute kidney injury by inhibiting necroptosis and inflammation. (PubMed, Int Immunopharmacol) - "Our findings revealed that AZD5423 strongly inhibits activation of RIPK3, and MLKL phosphorylation upon cisplatin-, hypoxia/reoxygenation (H/R)- and TNF-α stimuli as compared with GSK872, which is a previously identified RIPK3 inhibitor. Site-directed mutagenesis further revealed that AZD5423 reduces injury response via interacting with the key RIPK3 amino acid residues of Lys and Arg. In conclusion, our study has demonstrated that AZD5423 may serve as a potent inhibitor of RIPK3 kinase and a promising clinical candidate for AKI treatment."

Journal • Acute Kidney Injury • Cardiovascular • Immunology • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • TNFA

On the relationship between blend state and dispersibility of adhesive mixtures containing active pharmaceutical ingredients. (PubMed, Int J Pharm X) - "The objectives of this investigation were to study the evolution in blend state of adhesive mixtures containing the active pharmaceutical ingredients (APIs) salbutamol, budesonide and AZD5423 and to study the relationship between blend state and dispersibility of the mixtures, as assessed by the fine particle fraction (FPF). The adhesive mixtures of all APIs followed the three main states in terms of structural evolution and the overall shape of the FPF-fines concentration profiles could be explained by the evolution in blend state. It is proposed that the structure of the adhesion layer is an important factor explaining the differences in blend state - blend dispersibility relationships between the APIs."

Journal

Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review. (PubMed, J Exp Pharmacol) - "Several compounds are currently under pre-clinical development, but only three novel experimental GR agonists (GW870086X, AZD5423, AZD7594) seem to have some potential therapeutic relevance and have entered clinical trials for the treatment of asthma. Since data from pre-clinical studies have not always been confirmed in clinical investigations, well-designed randomized controlled trials are needed in asthmatic patients to confirm the potentially positive benefit/risk ratio of each specific SEGRA and to optimize the development strategy of these agents in respiratory medicine."

Journal • Review • Asthma • Immune Modulation • Inflammation • Respiratory Diseases

Pulmonary dissolution of poorly soluble compounds studied in an ex vivo rat lung model. (PubMed, Mol Pharm) - "To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused rat lung (IPL) model. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders, where AZD5423 had the poorest wettability, followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds."

Journal • Preclinical • Respiratory Diseases

Pharmacokinetics of the Inhaled Selective Glucocorticoid Receptor Modulator AZD5423 Following Inhalation Using Different Devices. (PubMed) - AAPS J - "The large difference in the estimated pulmonary bioavailability and the predicted lung deposited dose for AZD5423 implies an impact of mucociliary clearance. The lung absorption half-life indicates that AZD5423 is retained in the lung for a relatively short time."

Journal • Asthma • Biosimilar • Chronic Obstructive Pulmonary Disease • Immunology

Ranking in vitro dissolution of inhaled micronized drug powders including a candidate drug with two different particle sizes. (PubMed, Mol Pharm) - "Dissolution data was obtained on a series of micronized and aerosolized lipophilic DSs, budesonide, fluticasone furoate (FF), fluticasone propionate (FP), and AZD5423. Furthermore, a relation between in vitro dissolution rate (t63) and mean pulmonary absorption time in man (literature data) was observed, indicating clinical relevance. It is thus concluded that the method may be useful for the characterization and ranking of drug substances and drug products in early development, as well as being a potential tool for the control of dissolution as a potential quality attribute."

Journal • Preclinical