Delving into the Latest Updates on AZD-1305 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

AZD 1305, AZD1305

Target

L-type calcium channel x Nav1.5 x hERG

Action

blockers

Mechanism

L-type calcium channel blockers(Voltage-gated L-type calcium channel blockers), Nav1.5 blockers(Sodium channel protein type V alpha subunit blockers), hERG blockers(Voltage-gated potassium channel subunit Kv11.1 blockers)

Therapeutic Areas

Cardiovascular Diseases

Active Indication

Atrial Fibrillation

Inactive Indication

Atrial FlutterVentricular Dysfunction, Left

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization

Odense University HospitalAstraZeneca R&D Mölndal

Inactive Organization

AstraZeneca PLCAstraZeneca AB

License Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC22H31FN4O4

InChIKeyBLLNYXOLLAVTRF-UHFFFAOYSA-N

CAS Registry872045-91-5

This is a phase I, single-blind, randomized, placebo-controlled single and repeated ascending dose study to assess the safety, tolerability and pharmacokinetics with oral doses of AZD1305 extended-release capsules in healthy male Japanese and Caucasian subjects. Three (or four if needed) dose levels will be given to Japanese subjects and one of the doses will also be given to Caucasian subjects.

Start Date01 Jul 2009

Sponsor / Collaborator

AstraZeneca PLC

NCT00915356

/ CompletedPhase 2

A Double-blind, Randomised, Placebo-controlled, Multicentre, Dose-escalating Study of AZD1305 Given Intravenously for Cardioversion of Atrial Fibrillation

This study is being carried out to see which dose of AZD1305 is safe and effective in cardioverting atrial fibrillation into normal heart rhythm.

Start Date01 May 2009

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-1305

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100 Translational Medicine associated with AZD-1305

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100 Patents (Medical) associated with AZD-1305

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16

Literatures (Medical) associated with AZD-1305

01 Jul 2024·EBioMedicine

Advancing drug development for atrial fibrillation by prioritising findings from human genetic association studies

Article

Author: Providencia, Rui ; Lambiase, Pier D ; Finan, Chris ; Schilling, Richard ; Floriaan Schmidt, Amand ; Kukendrarajah, Kishore ; Farmaki, Aliki-Eleni

BACKGROUND:

Drug development for atrial fibrillation (AF) has failed to yield new approved compounds. We sought to identify and prioritise potential druggable targets with support from human genetics, by integrating the available evidence with bioinformatics sources relevant for AF drug development.

METHODS:

Genetic hits for AF and related traits were identified through structured search of MEDLINE. Genes derived from each paper were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured searches and review of evidence on MEDLINE and ClinialTrials.gov for each drug and its association with AF.

FINDINGS:

613 unique drugs were identified, with 21 already included in AF Guidelines. Cardiovascular drugs from classes not currently used for AF (e.g. ranolazine and carperitide) and anti-inflammatory drugs (e.g. dexamethasone and mehylprednisolone) had evidence of potential benefit. Further targets were considered druggable but remain open for drug development.

INTERPRETATION:

Our systematic approach, combining evidence from different bioinformatics platforms, identified drug repurposing opportunities and druggable targets for AF.

FUNDING:

KK is supported by Barts Charity grant G-002089 and is mentored on the AFGen 2023-24 Fellowship funded by the AFGen NIH/NHLBI grant R01HL092577. RP is supported by the UCL BHF Research Accelerator AA/18/6/34223 and NIHR grant NIHR129463. AFS is supported by the BHF grants PG/18/5033837, PG/22/10989 and UCL BHF Accelerator AA/18/6/34223 as well as the UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/Z000211/1 and by the UKRI-NIHR grant MR/V033867/1 for the Multimorbidity Mechanism and Therapeutics Research Collaboration. AF is supported by UCL BHF Accelerator AA/18/6/34223. CF is supported by UCL BHF Accelerator AA/18/6/34223.

01 Jun 2018·British Journal of Pharmacology

Human hepatocytes and cytochrome P450‐selective inhibitors predict variability in human drug exposure more accurately than human recombinant P450s

Article

Author: Lundahl, Anna ; Lindmark, Bo ; Andersson, Tommy B ; Isin, Emre M ; Kanebratt, Kajsa P

Background and Purpose:

Drugs metabolically eliminated by several enzymes are less vulnerable to variable compound exposure in patients due to drug–drug interactions (DDI) or if a polymorphic enzyme is involved in their elimination. Therefore, it is vital in drug discovery to accurately and efficiently estimate and optimize the metabolic elimination profile.

Experimental Approach:

CYP3A and/or CYP2D6 substrates with well described variability in vivo in humans due to CYP3A DDI and CYP2D6 polymorphism were selected for assessment of fraction metabolized by each enzyme (fmCYP) in two in vitro systems: (i) human recombinant P450s (hrP450s) and (ii) human hepatocytes combined with selective P450 inhibitors. Increases in compound exposure in poor versus extensive CYP2D6 metabolizers and by the strong CYP3A inhibitor ketoconazole were mathematically modelled and predicted changes in exposure were compared with in vivo data.

Key Results:

Predicted changes in exposure were within twofold of reported in vivo values using fmCYP estimated in human hepatocytes and there was a strong linear correlation between predicted and observed changes in exposure (r2 = 0.83 for CYP3A, r2 = 0.82 for CYP2D6). Predictions using fmCYP in hrP450s were not as accurate (r2 = 0.55 for CYP3A, r2 = 0.20 for CYP2D6).

Conclusions and Implications:

The results suggest that variability in human drug exposure due to DDI and enzyme polymorphism can be accurately predicted using fmCYP from human hepatocytes and CYP‐selective inhibitors. This approach can be efficiently applied in drug discovery to aid optimization of candidate drugs with a favourable metabolic elimination profile and limited variability in patients.

01 Oct 2017·British Journal of Pharmacology

Predicting QRS and PR interval prolongations in humans using nonclinical data

Article

Author: Collins, T ; Mettetal, J ; Parkinson, J ; Chappell, M J ; Bergenholm, L ; Evans, N D

Background and Purpose:

Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase.

Experimental Approach:

Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration‐matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model.

Key Results:

Meaningful (10%) human QRS/PR effects correlated with low levels of in vitro Nav1.5 block (3–7%) and Cav1.2 binding (13–21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3–4.6% and PR 2.3–10%), suggesting that worst‐case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data.

Conclusion and Implications:

Small changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non–arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies.

100 Deals associated with AZD-1305

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External Link

KEGG	Wiki	ATC	Drug Bank
-	AZD-1305	-	DB11766

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Ventricular Dysfunction, Left	Phase 2	Sweden	AstraZeneca PLC	01 Aug 2008
Atrial Fibrillation	Phase 2	Denmark	AstraZeneca AB	14 Dec 2007
Atrial Flutter	Phase 2	Denmark	AstraZeneca AB	14 Dec 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00915356 (CTgov)	Phase 2	Atrial Fibrillation	228	AZD1305 (AZD1305 Dose Group 1)	nrnrqplpnl(yjacgsfhwy) = dobjgvlwod eefifgnjlc (fipojxqqyy, kepsprdocw - ntngzalhgk) View more	-	01 Feb 2012
				AZD1305 (AZD1305 Dose Group 2)	nrnrqplpnl(yjacgsfhwy) = bljnxrejjf eefifgnjlc (fipojxqqyy, wyaxchhxad - pvkzascgnu) View more
NCT00643448 (CTgov)	Phase 2	Atrial Fibrillation	65	AZD1305 (AZD1305 Group A and AZD1305 Group B)	teujwztupt(flukueaoqb) = xvvljcyelm dtjiepsgoa (axdorsbbgk, aqayjnukcg - royhgsiubg) View more	-	26 Jan 2012
				Placebo+AZD1305 (Placebo)	teujwztupt(flukueaoqb) = uzcegggiie dtjiepsgoa (axdorsbbgk, hrjnucpykx - jbrxcggrcu) View more
NCT00915356 (Pubmed \| Europace)	Phase 2	Atrial Fibrillation	171	AZD1305	woswzlsvmj(wjazjzrrdg) = pduttgpzcm pqpouxcqsf (hmxlloeqzk ) View more	Negative	01 Aug 2011
NCT00748982 (CTgov)	Phase 2	Ventricular Dysfunction, Left	16	AZD1305 (AZD1305 Dose 1 and Dose 2)	xexbxawhaj(ptvypssqal) = xsaqkovkzc jfjqwarrrd (zxfzapkcyb, cpmxrgjsbz - qkcpotdexh) View more	-	13 Jun 2011
				Placebo (Placebo Dose 1 and Dose 2)	xexbxawhaj(ptvypssqal) = rtzgkbfgum jfjqwarrrd (zxfzapkcyb, mwerenvqgg - akooqbvzmk) View more