AICAR

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C9H15N4O8P
Molecular Weight	338.2112
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(=O)C1=C(N)N(C=N1)[C@@H]2O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]2O

InChI

InChIKey=NOTGFIUVDGNKRI-UUOKFMHZSA-N

InChI=1S/C9H15N4O8P/c10-7-4(8(11)16)12-2-13(7)9-6(15)5(14)3(21-9)1-20-22(17,18)19/h2-3,5-6,9,14-15H,1,10H2,(H2,11,16)(H2,17,18,19)/t3-,5-,6-,9-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.drugbank.ca/drugs/DB01700 | https://www.ncbi.nlm.nih.gov/pubmed/7744080 | https://www.ncbi.nlm.nih.gov/pubmed/18457469

AICAR (Acadesine) is an intermediate in the generation of inosine monophosphate. AICAR is an analog of adenosine monophosphate (AMP) that is capable of stimulating AMP-dependent protein kinase (AMPK) activity. AICAR has been used clinically to treat and protect against cardiac ischemic injury. The drug was first used in the 1980s as a method to preserve blood flow to the heart during surgery. The drug has also been shown as a potential treatment for diabetes by increasing the metabolic activity of tissues by changing the physical composition of muscle. Acadesine is an adenosine receptor agonist (ARA) in development for the treatment of ischaemia-reperfusion injury and chronic lymphocytic leukaemia. Schering-Plough is developing the compound as a cardioprotective agent in ischaemia-reperfusion injury. Avancell and Protherics are co-developing acadesine for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL). Clinical development is underway for both indications. AICAR, an AMPK activator, results in accumulation of ZMP, which mimics the stimulating effect of AMP on AMPK and AMPK kinase. Orphan drug status has been granted for acadesine in the EU for the treatment of B-cell chronic lymphocytic leukaemia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
AMP-activated protein kinase, AMPK 17 Target ID: CHEMBL2096907 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7744080 \| https://www.ncbi.nlm.nih.gov/pubmed/15694368	Activator 1430
Apoptosis 155 Target ID: map04210 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12522004 \| https://www.ncbi.nlm.nih.gov/pubmed/27847321 \| https://www.ncbi.nlm.nih.gov/pubmed/20664053	Activator 1430		380.0 µM [EC50]

Conditions

Condition	Modality	Highest Phase	Product
Lesch-Nyhan syndrome 1 Sources: https://clinicaltrials.gov/ct2/show/NCT00004314	Primary	Phase II 1132	Unknown Approved Use Unknown
Type 2 diabetes mellitus 259 Sources: https://clinicaltrials.gov/ct2/show/NCT00168519 http://adisinsight.springer.com/drugs/800001079	Primary	Phase I 428	Unknown Approved Use Unknown
Leukemia, B-cell, chronic 1 Sources: https://clinicaltrials.gov/ct2/show/NCT00559624 https://www.ncbi.nlm.nih.gov/pubmed/23228986	Primary	Phase II 1132	Unknown Approved Use Unknown
Myelodysplastic syndromes 58 Sources: https://clinicaltrials.gov/ct2/show/NCT01813838	Primary	Phase II 1132	Unknown Approved Use Unknown
Reperfusion injury in CABG surgery 1 Sources: https://clinicaltrials.gov/ct2/show/NCT00872001 https://www.ncbi.nlm.nih.gov/pubmed/18457469	Preventing	Phase III 656	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP19A1 60		CYP4F2 1 CYP4F11 1 CYP4A12 1 CYP4A11 4 CYP4F3 1 CYP4F2/3 1

Drug as perpetrator

Target	Modality	Activity
CYP19A1 60	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/743083#sid=144205104	no [IC50 26.6032 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=170465608	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=170465608	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346984#sid=144205104	no
CYP4A11 25	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/21205922/	no
CYP4A12 1	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/21205922/	no
CYP4F11 1	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/21205922/	no
CYP4F3 1	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/21205922/	no
CYP4F2 3	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/21205922/	yes
CYP4F2/3 1	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/21205922/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/23716168/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/588834#sid=144205104

PubMed

Title	Date	PubMed
Acadesine (AICA-riboside): disposition and metabolism of an adenosine-regulating agent.	1993 Oct	8227467
5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?	1995 Apr 15	7744080
AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle.	1997 Dec	9435525
The protective effect of acadesine on lung ischemia-reperfusion injury.	2001 Mar	11226083
Targeting the AMP-activated protein kinase for the treatment of type 2 diabetes.	2002 Jul	12476786
Protein kinase inhibitors block the stimulation of the AMP-activated protein kinase by 5-amino-4-imidazolecarboxamide riboside.	2002 Nov 6	12417310
AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase.	2003 Apr	12683939
Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes.	2003 May 1	12522004
AMP-activated protein kinase: the guardian of cardiac energy status.	2004 Aug	15314681
AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus.	2004 Mar	15009683
Intracerebroventricular infusion of glucose, insulin, and the adenosine monophosphate-activated kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, controls muscle glycogen synthesis.	2004 Sep	15192044
Acadesine induces apoptosis in B cells from mantle cell lymphoma and splenic marginal zone lymphoma.	2005 Feb	15549145
5-aminoimidazole-4-carboxamide riboside (AICAR) enhances GLUT2-dependent jejunal glucose transport: a possible role for AMPK.	2005 Jan 15	15367103
Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes.	2005 Jul 1	15878856
Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1.	2005 Jun	15864539
5-amino-imidazole carboxamide riboside acutely potentiates glucose-stimulated insulin secretion from mouse pancreatic islets by KATP channel-dependent and -independent pathways.	2005 May 20	15823553
Analysis of intracellular nucleotides by capillary electrophoresis-mass spectrometry.	2006	17065097
AMPK or ZMPK?	2006	16762515
A3 adenosine receptors and mitogen-activated protein kinases in lung injury following in vivo reperfusion.	2006	16623960
Moving preconditioning from bench to bedside.	2006 Jul 4	16814670
Adiponectin suppression of high-glucose-induced reactive oxygen species in vascular endothelial cells: evidence for involvement of a cAMP signaling pathway.	2006 Jun	16731851
Diagnosing AICA-ribosiduria by capillary electrophoresis.	2006 Oct 20	16798121
Ischemic preconditioning: protection against myocardial necrosis and apoptosis.	2007	18078014
Covariate heterogeneity in meta-analysis: criteria for deciding between meta-regression and individual patient data.	2007 Jul 10	17195960
5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNF{alpha}-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling.	2007 May	17513605
Acadesine: AICA riboside, ARA 100, arasine, GP 1 110.	2008	18457469
The need for a multi-level biochemical approach to defeat cancer that will also support the host.	2008 Oct	18752905
AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease.	2009 Apr	19275766
AICAR activates the pluripotency transcriptional network in embryonic stem cells and induces KLF4 and KLF2 expression in fibroblasts.	2009 Feb 12	19216758
Kinase activity-independent suppression of p73alpha by AMP-activated kinase alpha (AMPKalpha).	2009 Feb 19	19079340
Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators.	2009 Jan	18798311
Gateways to clinical trials.	2009 Mar	19455266
Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status.	2009 May	19190259
AMP-activated protein kinase enhances the expression of muscle-specific ubiquitin ligases despite its activation of IGF-1/Akt signaling in C2C12 myotubes.	2009 Oct 1	19639604
Germline deletion of AMP-activated protein kinase beta subunits reduces bone mass without altering osteoclast differentiation or function.	2010 Jan	19723702
Whole blood transcriptomics in cardiac surgery identifies a gene regulatory network connecting ischemia reperfusion with systemic inflammation.	2010 Oct 27	21048961

Patents

Sample Use Guides

In Vivo Use Guide

AICAR (Acadesine) 42 mg/kg diluted in normal saline to a total of 500 mL, delivered as an IV infusion over approximately 7 hours commencing within approximately 30 minutes before induction of anesthesia at a rate of 0.1 mg/kg/min (translating into 1.2 mL/min for a 500 mL solution). In addition, a 5 µg/mL cardioplegia solution of acadesine will be administered, and acadesine will be added to the priming solution (5 µg/mL) in the heart lung machine during CPB.

Route of Administration: Intravenous

In Vitro Use Guide

AICAR (Acadesine) (500 uM) increases the ZMP content in extracts of isolated hepatocytes after up to 30-40 min treatment, then remains fairly constant at approximately 4 nmol/g. Acadesine (500 uM) causes a transient 12-fold activation of AMPK at 15 min in rat hepatocytes and 2-3 fold activation of AMPK in adipocytes, without affecting levels of ATP, ADP or AMP. Acadesine (500 uM) causes a dramatic inhibition of both fatty acid and sterol synthesis in rat hepatocytes. Acadesine (500 uM) also causes a dramatic inactivation of HMG-CoA reductase.

Name

Type

Language

AICAR

Common Name

English

NSC-283955

Code

English

AMINOIMIDAZOLE CARBOXAMIDE RIBONUCLEOTIDE

Common Name

English

NSC-292227

Code

English

AICAR [MART.]

Common Name

English

AICA RIBONUCLEOTIDE

Common Name

English

Code System Code Type Description

CAS

3031-94-5