U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C11H14N4O4
Molecular Weight 266.2533
Optical Activity UNSPECIFIED
Defined Stereocenters 4 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of FORODESINE

SMILES

OC[C@H]1N[C@H]([C@H](O)[C@@H]1O)C2=CNC3=C2N=CNC3=O

InChI

InChIKey=IWKXDMQDITUYRK-KUBHLMPHSA-N
InChI=1S/C11H14N4O4/c16-2-5-9(17)10(18)7(15-5)4-1-12-8-6(4)13-3-14-11(8)19/h1,3,5,7,9-10,12,15-18H,2H2,(H,13,14,19)/t5-,7+,9-,10+/m1/s1

HIDE SMILES / InChI
Molecular Formula C11H14N4O4
Molecular Weight 266.2533
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 4 / 4
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: Description was created using several sources including: https://www.ncbi.nlm.nih.gov/pubmed/16778146 | http://investor.shareholder.com/biocryst/releasedetail.cfm?releaseid=179991 | https://www.ncbi.nlm.nih.gov/pubmed/17016779 | https://clinicaltrials.gov/ct2/show/NCT00289562 | http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006254.pdf

Forodesine hydrochloride is the salt of the synthetic high-affinity transition-state analog forodesine (BCX-1777, immucillin-H), a substrate designed to mimic the properties or the geometry of the transition state of reaction. It is an anticancer drug that has been developed for the treatment of different hematologic malignancies. In December 2006, orphan designation (EU/3/06/421) was granted by the European Commission to Napp Pharmaceuticals Research Limited, United Kingdom, for forodesine hydrochloride for the treatment of acute lymphoblastic leukemia. Forodesine hydrochloride has been evaluated in Phase I/Phase II clinical trials for several cancer types including chronic lymphocytic leukemia (CLL), B-Cell acute lymphoblastic leukemia and refractory cutaneous T-cell lymphoma (CTCL). Forodesine is a potent purine nucleoside phosphorylase (PNP) inhibitor that acts by elevating plasma 2'-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate, which in turn affects deoxynucleotide-triphosphate pools and induces cell death by apoptosis. Forodesine in the presence of dGuo inhibited the proliferation of CEM-SS (T-acute lymphoblastic leukemia) cells with an IC50 of 0.015 uM. This inhibition by forodesine and dGuo was accompanied by a 154-fold and 8-fold elevation of endogenous dGuo triphosphate (dGTP) and deoxyadenosine triphosphate (dATP) pools, respectively. Cytotoxic activity of forodesine in the presence of dGuo was selective to T lymphocytes. It is a 10- to 100-fold more potent inhibitor of human lymphocyte proliferation than other known PNP inhibitors such as PD141955 and BCX-34.8

Originator

Albert Einstein College of Medicine
2
Curator's Comment: Discovered by scientists at Albert Einstein College of Medicine forodesine has been further developed by BioCryst Pharmaceuticals, Inc.

Approval Year

Unknown
139594
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8297
 23.0 pM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
328 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
300 mg single, oral
dose: 300 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
335.3 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
216.5 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
421.6 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
300 mg 1 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
499 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
200 mg 1 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
139.2 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
100 mg single, oral
dose: 100 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
4596 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
300 mg single, oral
dose: 300 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
4608 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
2730 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
5587 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
300 mg 1 times / day steady-state, oral
dose: 300 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
6303 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
200 mg 1 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
1948 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
100 mg single, oral
dose: 100 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
14.4 h
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
300 mg single, oral
dose: 300 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
14.1 h
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
200 mg single, oral
dose: 200 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
13 h
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/22448814/
100 mg single, oral
dose: 100 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
FORODESINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FED
Doses

Doses

DosePopulationAdverse events​
300 mg 1 times / day steady-state, oral
Highest studied dose
Dose: 300 mg, 1 times / day
Route: oral
Route: steady-state
Dose: 300 mg, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
unhealthy
n = 5
Health Status: unhealthy
Condition: refractory peripheral T/natural killer-cell malignancies
Sex: M+F
Food Status: FED
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
Other AEs: anemia...
Other AEs:
anemia (grade 4, 1 pt)
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
100 mg 1 times / day steady-state, oral
Studied dose
Dose: 100 mg, 1 times / day
Route: oral
Route: steady-state
Dose: 100 mg, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
unhealthy
n = 5
Health Status: unhealthy
Condition: refractory peripheral T/natural killer-cell malignancies
Sex: M+F
Food Status: FED
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
Disc. AE: Herpes zoster...
Other AEs: Lymphopenia...
AEs leading to
discontinuation/dose reduction:
Herpes zoster (grade 3, 1 pt)
Other AEs:
Lymphopenia (grade 4, 2 patients)
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
200 mg 1 times / day steady-state, oral
Studied dose
Dose: 200 mg, 1 times / day
Route: oral
Route: steady-state
Dose: 200 mg, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
unhealthy
n = 3
Health Status: unhealthy
Condition: refractory peripheral T/natural killer-cell malignancies
Sex: M+F
Food Status: FED
Population Size: 3
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
Disc. AE: cellulitis...
Other AEs: Lymphopenia...
AEs leading to
discontinuation/dose reduction:
cellulitis (serious, 1 pt)
Other AEs:
Lymphopenia (grade 4, 2 patients)
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
AEs

AEs

AESignificanceDosePopulation
anemia grade 4, 1 pt
300 mg 1 times / day steady-state, oral
Highest studied dose
Dose: 300 mg, 1 times / day
Route: oral
Route: steady-state
Dose: 300 mg, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
unhealthy
n = 5
Health Status: unhealthy
Condition: refractory peripheral T/natural killer-cell malignancies
Sex: M+F
Food Status: FED
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
Herpes zoster grade 3, 1 pt
Disc. AE
100 mg 1 times / day steady-state, oral
Studied dose
Dose: 100 mg, 1 times / day
Route: oral
Route: steady-state
Dose: 100 mg, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
unhealthy
n = 5
Health Status: unhealthy
Condition: refractory peripheral T/natural killer-cell malignancies
Sex: M+F
Food Status: FED
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
Lymphopenia grade 4, 2 patients
100 mg 1 times / day steady-state, oral
Studied dose
Dose: 100 mg, 1 times / day
Route: oral
Route: steady-state
Dose: 100 mg, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
unhealthy
n = 5
Health Status: unhealthy
Condition: refractory peripheral T/natural killer-cell malignancies
Sex: M+F
Food Status: FED
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
Lymphopenia grade 4, 2 patients
200 mg 1 times / day steady-state, oral
Studied dose
Dose: 200 mg, 1 times / day
Route: oral
Route: steady-state
Dose: 200 mg, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
unhealthy
n = 3
Health Status: unhealthy
Condition: refractory peripheral T/natural killer-cell malignancies
Sex: M+F
Food Status: FED
Population Size: 3
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
cellulitis serious, 1 pt
Disc. AE
200 mg 1 times / day steady-state, oral
Studied dose
Dose: 200 mg, 1 times / day
Route: oral
Route: steady-state
Dose: 200 mg, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
unhealthy
n = 3
Health Status: unhealthy
Condition: refractory peripheral T/natural killer-cell malignancies
Sex: M+F
Food Status: FED
Population Size: 3
Sources:
https://pubmed.ncbi.nlm.nih.gov/22448814/
PubMed

PubMed

TitleDatePubMed
One-third-the-sites transition-state inhibitors for purine nucleoside phosphorylase.
1998 Jun 16
Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes.
2001 Apr 10
Purine nucleoside phosphorylase as a cytosolic arsenate reductase.
2002 Nov
Arsenate reduction in human erythrocytes and rats--testing the role of purine nucleoside phosphorylase.
2003 Jul
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase works as an arsenate reductase in human red blood cells and rat liver cytosol.
2005 Jun
Syntheses and bio-activities of the L-enantiomers of two potent transition state analogue inhibitors of purine nucleoside phosphorylases.
2006 Mar 21
Drug evaluation: forodesine - PNP inhibitor for the treatment of leukemia, lymphoma and solid tumor.
2006 Oct
Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells.
2006 Oct 1
Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM.
2009 Aug 20
Patents

Patents

US2011130412
2
US2015191472
2

Sample Use Guides

In Vivo Use Guide
Forodesine (200 mg/day) for up to 24 weeks in patients with advanced, fludarabine-treated chronic lymphocytic leukemia
Route of Administration: Oral
In Vitro Use Guide
Primary human CLL lymphocytes were incubated on the same day of their isolation from blood with or without 2 uM forodesine and 10 uM dGuo for 0, 4, 8, 16, and 24 hours. The nucleotides in the leukemia cells were extracted by 60% methanol and the dNTPs were quantitated by DNA polymerase assay in these cell extracts. CLL cells showed a wide variation in the accumulation of intracellular dGTP without any effect on other deoxynucleotides.
Substance Class Chemical
Created
by admin
on Fri Dec 15 15:40:16 UTC 2023
Edited
by admin
on Fri Dec 15 15:40:16 UTC 2023
Record UNII
426X066ELK
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
FORODESINE
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
Immucillin H
Common Name English
BCX-1777
Code English
FORODESINE [USAN]
Common Name English
FODOSINE
Brand Name English
Mundesine
Brand Name English
FORODESINE [MI]
Common Name English
forodesine [INN]
Common Name English
Forodesine [WHO-DD]
Common Name English
(-)-7-[(2S,3S,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-1,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
Systematic Name English
4H-PYRROLO(3,2-D)PYRIMIDIN-4-ONE, 7-((2S,3S,4R,5R)-3,4-DIHYDROXY-5-(HYDROXYMETHYL)-2-PYRROLIDINYL)-1,5-DIHYDRO-
Systematic Name English
NSC-717904
Code English
Classification Tree Code System Code
NCI_THESAURUS C2151
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
EU-Orphan Drug EU/3/10/780
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
Code System Code Type Description
DRUG BANK
DB06185
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
PUBCHEM
135409409
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
CAS
209799-67-7
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
SMS_ID
100000128117
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
WIKIPEDIA
FORODESINE
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
NCI_THESAURUS
C65755
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
ChEMBL
CHEMBL218291
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
INN
8558
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
USAN
RR-24
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
EVMPD
SUB34832
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
DRUG CENTRAL
5229
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
MERCK INDEX
m12041
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
NSC
717904
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
FDA UNII
426X066ELK
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
MESH
C113101
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
EPA CompTox
DTXSID50943276
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
CHEBI
43362
Created by admin on Fri Dec 15 15:40:16 UTC 2023 , Edited by admin on Fri Dec 15 15:40:16 UTC 2023
PRIMARY
Related Record Type Details
Structure of FORODESINE HYDROCHLORIDE
SALT/SOLVATE -> PARENT
PURINE NUCLEOSIDE PHOSPHORYLASE
TARGET -> INHIBITOR
Related Record Type Details
Structure of FORODESINE
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