Delving into the Latest Updates on AZD-5672 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

CCR5

Mechanism

CCR5 antagonists(C-C chemokine receptor type 5 antagonists)

Therapeutic Areas

Immune System DiseasesSkin and Musculoskeletal DiseasesUrogenital Diseases

Active Indication-

Inactive Indication

Renal InsufficiencyRheumatoid Arthritis

Originator Organization

AstraZeneca PLC

Active Organization-

Inactive Organization

AstraZeneca PLC

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC31H43F2N3O5S2

InChIKeyQOSMEMHKXNNIGG-SSEXGKCCSA-N

CAS Registry872879-86-2

A nickel complex of isoquinox promoted enantioselective conjugate arylation and heteroarylation of enones using aryl and heteroaryl halides directly. The reaction was successfully applied to stereoselective syntheses of ar-turmerone, chiral fragments of (+)-tolterodine and AZD5672. Mechanistically, experiments and calculations supported that an arylnickel(I) complex inserted to enones via an elementary 1,4-addition.

01 Jun 2018·Journal of Pharmacokinetics and PharmacodynamicsQ3 · MEDICINE

Assessing QT/QTc interval prolongation with concentration-QT modeling for Phase I studies: impact of computational platforms, model structures and confidence interval calculation methods

Q3 · MEDICINE

Article

Author: Lu, Jingtao ; Al-Huniti, Nidal ; Helmlinger, Gabriel ; Li, Jianguo

Modeling the relationship between drug concentrations and heart rate corrected QT interval (QTc) change from baseline (C-∆QTc), based on Phase I single ascending dose (SAD) or multiple ascending dose (MAD) studies, has been proposed as an alternative to thorough QT studies (TQT), in assessing drug-induced QT prolongation risk. The present analysis used clinical SAD, MAD and TQT study data of an experimental compound, AZD5672, to evaluate the performance of: (i) three computational platforms (linear mixed-effects modeling implemented via PROC MIXED in SAS, as well as in R using LME4 package and linear quantile mixed models (LQMM) implemented via LQMM package; (ii) different model structures with and without treatment- or time-specific intercepts; and (iii) three methods for calculating the confidence interval (CI) of QTc prolongation (analytical and bootstrap methods with fixed or varied geometric mean concentrations). We show that treatment- and time-specific intercepts may need to be included into C-∆QTc modeling through PROC MIXED or LME4, regardless of their statistical significance. With the intersection union test (IUT) in the TQT study as a reference for comparison, inclusion of these intercepts increased the feasibility for C-∆QTc modelling of SAD or MAD to reach the same conclusion as the IUT analysis based on TQT study. Compared to PROC MIXED or LME4, the LQMM method is less dependent on inclusion of treatment- or time-specific intercepts, and the bootstrap CI calculation methods provided higher likelihood for C-∆QTc modeling of SAD and MAD studies to reach the same conclusion as the IUT based on the TQT study.

01 Feb 2012·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis

Q4 · MEDICINE

Article

Author: John Shaw ; John G. Cumming ; Alan Faull ; Adrian Highton ; Howard Tucker ; Martin Wild ; John Oldfield ; Colin Fielding ; Stuart Wells ; Dearg Brown

Modifications to a series of potent and selective substituted 1-(3,3-diphenylpropyl)-piperidine phenylacetamide CCR5 antagonists were explored with the aim of reducing affinity at the hERG cardiac ion channel. Replacement of one aromatic ring in the diphenylpropyl region with less lipophilic, saturated heterocyclic rings and subsequent optimisation of the other phenyl ring led to the identification of clinical compound AZD5672 which retained excellent potency while reducing hERG affinity. Modulating lipophilicity affected the interplay between potency, hERG affinity and absorption. AZD5672 was found to have an acceptable balance of these properties and was progressed to a phase II clinical trial to test the hypothesis that inhibition of CCR5 will bring benefits in the treatment of rheumatoid arthritis.

100 Deals associated with AZD-5672

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11804

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 2	IT	AstraZeneca PLC	01 Jul 2008
Rheumatoid Arthritis	Phase 2	HU	AstraZeneca PLC	01 Jul 2008
Rheumatoid Arthritis	Phase 2	SK	AstraZeneca PLC	01 Jul 2008
Rheumatoid Arthritis	Phase 2	RS	AstraZeneca PLC	01 Jul 2008
Rheumatoid Arthritis	Phase 2	RO	AstraZeneca PLC	01 Jul 2008
Rheumatoid Arthritis	Phase 2	CZ	AstraZeneca PLC	01 Jul 2008
Rheumatoid Arthritis	Phase 2	PL	AstraZeneca PLC	01 Jul 2008
Rheumatoid Arthritis	Discovery	ZA	AstraZeneca PLC	01 Jul 2008
Rheumatoid Arthritis	Discovery	RU	AstraZeneca PLC	01 Jul 2008
Rheumatoid Arthritis	Discovery	BG	AstraZeneca PLC	01 Jul 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00713544 (ESCAPE, CTgov)	Phase 2	Rheumatoid Arthritis	373	AZD5672 (AZD5672 20 mg)	qrnxnljfjw(snblpekmtq) = gchpzfrdzo fgotggaulu (oghmonwtzz, lfestgwoff - dhuazuohsi) View more	-	03 Oct 2011
				AZD5672 (AZD5672 50 mg)	qrnxnljfjw(snblpekmtq) = zupopvkcqe fgotggaulu (oghmonwtzz, hownzdaoxg - tcvvceluca) View more