FORODESINE HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C11H14N4O4.ClH
Molecular Weight	302.714
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=WEIAMZKHBCLFOG-QPAIBFMUSA-N

InChI=1S/C11H14N4O4.ClH/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);1H/t5-,7+,9-,10+;/m1./s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11287638/
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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Purine nucleoside phosphorylase 5 Target ID: CHEMBL2215 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC31879/	Inhibitor 8297		23.0 pM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
B-cell acute lymphoblastic leukemia 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00289562 http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006254.pdf	Primary	Phase II 1132	Unknown Approved Use Unknown
Leukemia, T-cell 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00095381	Primary	Phase II 1132	Unknown Approved Use Unknown
Leukemia, lymphocytic, chronic 2 Sources: https://clinicaltrials.gov/ct2/show/NCT00289549 https://www.ncbi.nlm.nih.gov/pubmed/20427701	Primary	Phase II 1132	Unknown Approved Use Unknown
Cutaneous T-cell lymphoma 9 Sources: https://clinicaltrials.gov/ct2/show/NCT00061880	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
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

Value	Dose	Analyte	Population
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

T_1/2

Value	Dose	Analyte	Population
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

Dose	Population	Adverse 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

AE	Significance	Dose	Population
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

Title	Date	PubMed
One-third-the-sites transition-state inhibitors for purine nucleoside phosphorylase.	1998 Jun 16	9628722
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase works as an arsenate reductase in human red blood cells and rat liver cytosol.	2005 Jun	15788719
Syntheses and bio-activities of the L-enantiomers of two potent transition state analogue inhibitors of purine nucleoside phosphorylases.	2006 Mar 21	16525558
Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells.	2006 Oct 1	16778146
Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM.	2009 Aug 20	19541822

Patents

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.

Name

Type

Language

FORODESINE HYDROCHLORIDE

Official 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-, MONOHYDROCHLORIDE

Common Name

English

FORODESINE HYDROCHLORIDE [MI]

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 MONOHYDROCHLORIDE

Systematic Name

English

FORODESINE HYDROCHLORIDE [JAN]

Common Name

English

Forodesine Hydrochloride [WHO-DD]

Common Name

English

FORODESINE HCL

Common Name

English

FORODESINE HYDROCHLORIDE [USAN]

Common Name

English

FORODESINE HYDROCHLORIDE [MART.]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

190504