AZD-1480

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C14H14ClFN8
Molecular Weight	348.766
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@H](NC1=NC=C(Cl)C(NC2=NNC(C)=C2)=N1)C3=NC=C(F)C=N3

InChI

InChIKey=PDOQBOJDRPLBQU-QMMMGPOBSA-N

InChI=1S/C14H14ClFN8/c1-7-3-11(24-23-7)21-13-10(15)6-19-14(22-13)20-8(2)12-17-4-9(16)5-18-12/h3-6,8H,1-2H3,(H3,19,20,21,22,23,24)/t8-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C14H14ClFN8
Molecular Weight	348.766
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22829094 | https://www.ncbi.nlm.nih.gov/pubmed/23847256https://www.ncbi.nlm.nih.gov/pubmed/23847256
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/19962667 | https://www.ncbi.nlm.nih.gov/pubmed/25504635

AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). In phase I study, AZD1480 was administered as an oral QD or b.i.d. monotherapy to patients with advanced solid tumors at eight dose levels in the ranges of 10–70 mg QD and 20–45 mg b.i.d. using a standard 3+3 design. AZD1480 had fast absorption, fast elimination, and dose-dependent increase in exposure from 10 mg to 50 mg. Unusual toxicity profile and overall lack of clinical activity led to discontinuation of development of AZD1480.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tyrosine-protein kinase JAK2 53 Target ID: CHEMBL2971 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22829094 \| https://www.ncbi.nlm.nih.gov/pubmed/21138246	Inhibitor 8228
Tyrosine-protein kinase JAK2 53 Target ID: CHEMBL1075225 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19962667	Inhibitor 8228		0.26 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Solid tumors 144 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23847256 https://clinicaltrials.gov/ct2/show/NCT01112397	Primary	Phase I 424	Unknown Approved Use Unknown
Myeloproliferative disorders 2 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23847256 http://adisinsight.springer.com/drugs/800030336 https://clinicaltrials.gov/ct2/show/NCT00910728	Primary	Phase I 424	Unknown Approved Use Unknown
Primary myelofibrosis 6 Sources: https://clinicaltrials.gov/ct2/show/NCT00910728	Primary	Phase I 424	Unknown Approved Use Unknown
Post-polycythaemia vera 1 Sources: https://clinicaltrials.gov/ct2/show/NCT00910728	Primary	Phase I 424	Unknown Approved Use Unknown
Essential thrombocythemia 1 Sources: https://clinicaltrials.gov/ct2/show/NCT00910728	Primary	Phase I 424	Unknown Approved Use Unknown
Hepatocellular carcinoma 83 Sources: https://clinicaltrials.gov/ct2/show/NCT01219543	Primary	Phase I 424	Unknown Approved Use Unknown

AUC

Value	Dose	Co-administered	Analyte	Population
57.6 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21138246	10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		AZD-1480 plasma	Mus musculus population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21138246	10 mg/kg single, oral dose: 10 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		AZD-1480 plasma	Mus musculus population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1437

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1626	inhibitor 3240 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363677143	yes

PubMed

Title	Date	PubMed
Effects of the JAK2 inhibitor, AZ960, on Pim/BAD/BCL-xL survival signaling in the human JAK2 V617F cell line SET-2.	2008 Nov 21	18775810
Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway.	2011 Jan 13	21138246
Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3.	2011 May 26	21486047

Patents

Sample Use Guides

In Vivo Use Guide

AZD-1480 was administered as an oral QD or b.i.d. monotherapy to patients with advanced solid tumors at eight dose levels in the ranges of 10–70 mg QD and 20– 45 mg b.i.d. using a standard 3 3 design.

Route of Administration: Oral

In Vitro Use Guide

AZD-1480 at low doses (0.1–1 uM) inhibited constitutive STATs phosphorylation in HL cell lines, demonstrating immunoregulatory effects as it downregulated the surface expression of the STAT3-target immunosuppressive cell-surface protein PD-L1 and PD-L2, in addition to downregulation of IL-13, IL-6 and TARC. At higher concentration (5 uM), AZD-1480 induced antiproliferative effects in HL cell lines in a JAK/ STAT-independent manner.

Substance Class	Chemical Created by `admin` on `Thu Jul 06 07:46:10 UTC 2023` Edited by `admin` on `Thu Jul 06 07:46:10 UTC 2023`
Record UNII	KL2Z2TLF01
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

AZD-1480

Common Name

English

AZD1480

Code

English

2,4-PYRIMIDINEDIAMINE, 5-CHLORO-N2-((1S)-1-(5-FLUORO-2-PYRIMIDINYL)ETHYL)-N4-(5-METHYL-1H-PYRAZOL-3-YL)-

Systematic Name

English

AZD 1480 [WHO-DD]

Common Name

English

Code System Code Type Description

FDA UNII

KL2Z2TLF01