Delving into the Latest Updates on AZD-5423 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

GR

Action

agonists

Mechanism

GR agonists(Glucocorticoid receptor agonists)

Therapeutic Areas

Immune System DiseasesRespiratory Diseases

Active Indication

Asthma

Inactive Indication

Allergic asthmaPulmonary Disease, Chronic Obstructive

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization

AstraZeneca AB

McMaster University

Inactive Organization

AstraZeneca PLC

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC25H21F4N3O3

InChIKeyFCNQMDSJHADDFT-WNSKOXEYSA-N

CAS Registry1034148-04-3

The purpose of this study is to assess safety, tolerability, pharmacokinetics and pharmacodynamic effects (24-hours plasma cortisol area under curve, plasma cortisol pre and post ACTH stimulation, dehydroepiandrosterone sulphate (DHEAS), osteocalcin and 24 hours urine cortisol) of AZD5423 following administration of single and multiple ascending doses in healthy male Japanese subjects.

Start Date01 Jun 2011

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-5423

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100 Translational Medicine associated with AZD-5423

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100 Patents (Medical) associated with AZD-5423

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24

Literatures (Medical) associated with AZD-5423

01 Dec 2024·Purinergic Signalling

Machine learning-aided search for ligands of P2Y6 and other P2Y receptors

Article

Author: Gao, Zhan-Guo ; Lewicki, Sarah A ; Puhl, Ana C ; Ekins, Sean ; Makarov, Vadim ; Jacobson, Kenneth A ; Pramanik, Asmita

AbstractThe P2Y6 receptor, activated by uridine diphosphate (UDP), is a target for antagonists in inflammatory, neurodegenerative, and metabolic disorders, yet few potent and selective antagonists are known to date. This prompted us to use machine learning as a novel approach to aid ligand discovery, with pharmacological evaluation at three P2YR subtypes: initially P2Y6 and subsequently P2Y1 and P2Y14. Relying on extensive published data for P2Y6R agonists, we generated and validated an array of classification machine learning model using the algorithms deep learning (DL), adaboost classifier (ada), Bernoulli NB (bnb), k-nearest neighbors (kNN) classifier, logistic regression (lreg), random forest classifier (rf), support vector classification (SVC), and XGBoost (XGB) classifier models, and the common consensus was applied to molecular selection of 21 diverse structures. Compounds were screened using human P2Y6R-induced functional calcium transients in transfected 1321N1 astrocytoma cells and fluorescent binding inhibition at closely related hP2Y14R expressed in CHO cells. 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.

31 Dec 2022·Journal of Enzyme Inhibition and Medicinal ChemistryQ2 · MEDICINE

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors

Q2 · MEDICINE

ArticleOA

Author: Feng, Siqi ; Wang, Yuyang ; Huang, Tao ; Wang, Longfei ; Yao, Yongfang ; Cheng, Weyland ; Duan, Yongtao ; Yang, Longhua

The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC₅₀=25.6 µM, anti-angiogenesis in Zebrafish: IC₅₀=38.4 µM, anti-proliferation against K562 and Jurkat: IC₅₀=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC₅₀=4.8 µM and anti-angiogenesis in Zebrafish: IC₅₀=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC₅₀= 0.09-1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.

05 Dec 2022·Journal of Biomolecular Structure and Dynamics

Drug repositioning to propose alternative modulators for glucocorticoid receptor through structure-based virtual screening

Article

Author: Akten, Ebru Demet ; Metin, Reyhan

Drug repositioning has recently become one of the widely used drug design approaches in proposing alternative compounds with potentially fewer side effects. In this study, structure-based pharmacophore modelling and docking was used to screen existing drug molecules to bring forward potential modulators for ligand-binding domain of human glucocorticoid receptor (hGR). There exist several drug molecules targeting hGR, yet their apparent side effects still persist. Our goal was to disclose new compounds via screening existing drug compounds to bring forward fast and explicit solutions. The so-called shared pharmacophore model was created using the most persistent pharmacophore features shared by several crystal structures of the receptor. The shared model was first used to screen a small database of 75 agonists and 300 antagonists/decoys, and exhibited a successful outcome in its ability to distinguish agonists from antagonists/decoys. Then, it was used to screen a database of over 5000 molecules composed of FDA-approved, worldwide used and investigational drug compounds. A total of 110 compounds satisfying the pharmacophore requirements were subjected to different docking experiments for further assessment of their binding ability. In the final hit list of 54 compounds which fulfilled all scoring criteria, 19 of them were nonsteroidal and when further investigated, each presented a unique scaffold with little structural resemblance to any known nonsteroidal GR modulators. Independent 100 ns long MD simulations conducted on three selected drug candidates in complex with hGR displayed stable conformations incorporating several hydrogen bonds common to all three compounds and the reference molecule dexamethasone.Communicated by Ramaswamy H. Sarma.

100 Deals associated with AZD-5423

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External Link

KEGG	Wiki	ATC	Drug Bank
-	AZD-5423	-	DB12280

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	Canada	McMaster University	15 Jan 2015
Pulmonary Disease, Chronic Obstructive	Discovery	Russia	AstraZeneca PLC	01 Apr 2012
Pulmonary Disease, Chronic Obstructive	Discovery	Hungary	AstraZeneca PLC	01 Apr 2012
Pulmonary Disease, Chronic Obstructive	Discovery	Bulgaria	AstraZeneca PLC	01 Apr 2012
Pulmonary Disease, Chronic Obstructive	Discovery	Italy	AstraZeneca PLC	01 Apr 2012
Pulmonary Disease, Chronic Obstructive	Discovery	Poland	AstraZeneca PLC	01 Apr 2012
Pulmonary Disease, Chronic Obstructive	Discovery	Slovakia	AstraZeneca PLC	01 Apr 2012
Pulmonary Disease, Chronic Obstructive	Discovery	Ukraine	AstraZeneca PLC	01 Apr 2012
Pulmonary Disease, Chronic Obstructive	Discovery	France	AstraZeneca PLC	01 Apr 2012
Allergic asthma	Discovery	Canada	AstraZeneca PLC	01 Nov 2010