FOSMIDOMYCIN

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C4H10NO5P
Molecular Weight	183.0997
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

ON(CCCP(O)(O)=O)C=O

InChI

InChIKey=GJXWDTUCERCKIX-UHFFFAOYSA-N

InChI=1S/C4H10NO5P/c6-4-5(7)2-1-3-11(8,9)10/h4,7H,1-3H2,(H2,8,9,10)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12937969
Curator's Comment: The description was created based on several sources, including https://www.drugbank.ca/drugs/DB02948 | https://clinicaltrials.gov/ct2/show/NCT00214643 | https://clinicaltrials.gov/ct2/show/NCT00217451 | https://www.ncbi.nlm.nih.gov/pubmed/21866890

Fosmidomycin (3-(formylhydroxyamino)-propylphosphonic acid mono-sodium salt, 3-(N-formyl-N-hydroxyamino)-propylphosphonic acid mono-sodium salt, FR-31564) is a potent inhibitor of P. falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR), developed by Albert Schweitzer Hospital for P. falciparum malaria treatment. Fosmidomycin was originally isolated as natural antibiotic from Streptomyces lavendulae. Fosmidomycin is active against a broad range of enterobacteria, but not against Gram-positive organisms or anaerobes. Fosmidomycin was developed as far as an early phase II study for the treatment of urinary tract infections by Fujisawa Pharmaceutical Company (Osaka, Japan) in the early eighties, but these trials have been discontinued. In recent clinical studies, it was shown that fosmidomycin is effective in curing uncomplicated Plasmodium falciparum malaria in humans. The treatment was well tolerated and resulted in a fast parasite and fever clearance. However, the high rate of recrudescence precludes the use of fosmidomycin as a monotherapy. In drug combination studies, the synergy of fosmidomycin with clindamycin was observed. Clinical studies with a fosmidomycin-clindamycin combination are currently ongoing.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplastic 2 Target ID: O96693 Gene ID: NA Gene Symbol: DXR Target Organism: Plasmodium falciparum (isolate HB3) Sources: https://www.ncbi.nlm.nih.gov/pubmed/12937969	Inhibitor 8504		28.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Malaria 96 Sources: https://clinicaltrials.gov/ct2/show/NCT00214643	Primary		Phase III 665	Unknown Approved Use Unknown
Urinary tract infections 207 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12937969	Primary		Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
4.58 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17531088	1200 mg 3 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	FOSMIDOMYCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
11.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	7.5 mg/kg single, intramuscular dose: 7.5 mg/kg route of administration: Intramuscular experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
2.33 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
27.67 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17531088	1200 mg 3 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	FOSMIDOMYCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
210 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	30 mg/kg single, intravenous dose: 30 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
42.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	7.5 mg/kg single, intramuscular dose: 7.5 mg/kg route of administration: Intramuscular experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
14 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
0.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17531088	1200 mg 3 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	FOSMIDOMYCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1.65 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	30 mg/kg single, intravenous dose: 30 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
1.58 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	7.5 mg/kg single, intramuscular dose: 7.5 mg/kg route of administration: Intramuscular experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
1.87 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7073262	500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered:	FOSMIDOMYCIN serum	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
99% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17531088	1200 mg 3 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		FOSMIDOMYCIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Sourcing

Vendor/Aggregator	ID	URL
AK Scientific	R980	https://aksci.com/item_detail.php?cat=R980
ApexBio Technology	C4898	https://www.apexbt.com/catalogsearch/result/?q=C4898
BOC Sciences	66508-53-0	http://www.bocsci.com/description.asp?cas=66508-53-0
Cayman Chemical	16000	http://www.caymanchem.com/app/template/Product.vm/catalog/16000
Chemspace	CSC000076817	https://chem-space.com/CSC000076817
eMolecules	300143136	https://orderbb.emolecules.com/search/#?query=300143136
eMolecules	50153329	https://orderbb.emolecules.com/search/#?query=50153329
eMolecules	8321444	https://orderbb.emolecules.com/search/#?query=8321444
Enamine	BBV-38278542	http://www.enaminestore.com/catalog/BBV-38278542
MuseChem	I006850	https://www.musechem.com/product/I006850.html
Toronto Research Chemicals	C176670	https://www.trc-canada.com/product-detail/?CatNum=C176670
Toronto Research Chemicals	F728500	https://www.trc-canada.com/product-detail/?CatNum=F728500

PubMed

Title	Date	PubMed
1-Deoxy-D-xylulose 5-phosphate reductoisomerase and plastid isoprenoid biosynthesis during tomato fruit ripening.	2001 Aug	11532167
Diaryl ester prodrugs of FR900098 with improved in vivo antimalarial activity.	2001 Mar 26	11277531
Expression and molecular analysis of the Arabidopsis DXR gene encoding 1-deoxy-D-xylulose 5-phosphate reductoisomerase, the first committed enzyme of the 2-C-methyl-D-erythritol 4-phosphate pathway.	2002 Aug	12177470
Elucidation of the methylerythritol phosphate pathway for isoprenoid biosynthesis in bacteria and plastids. A metabolic milestone achieved through genomics.	2002 Nov	12427975
Natural abundance carbon isotope composition of isoprene reflects incomplete coupling between isoprene synthesis and photosynthetic carbon flow.	2003 Apr	12692331
The methylerythritol phosphate pathway and its significance as a novel drug target.	2003 Aug	14529427
Methyl palmitate: a novel product of the Medfly (Ceratitis capitata) corpus allatum.	2003 Dec	14599501
Fosmidomycin for the treatment of malaria.	2003 Jun	12937969
Role of the non-mevalonate pathway in indole alkaloid production by Catharanthus roseus hairy roots.	2003 May-Jun	12790690
New antimalarial drugs.	2003 Nov 10	14613157
The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin.	2003 Sep 15	14514358
Impact of ozone on monoterpene emissions and evidence for an isoprene-like antioxidant action of monoterpenes emitted by Quercus ilex leaves.	2004 Apr	14757575
13C labeling reveals chloroplastic and extrachloroplastic pools of dimethylallyl pyrophosphate and their contribution to isoprene formation.	2004 Aug	15286296
The methylerythritol phosphate pathway is functionally active in all intraerythrocytic stages of Plasmodium falciparum.	2004 Dec 10	15452112
Determination of fosmidomycin in human serum and urine by capillary electrophoresis.	2004 Jul 5	15171936
Substrate analogs for the investigation of deoxyxylulose 5-phosphate reductoisomerase inhibition: synthesis and evaluation.	2004 Nov 1	15454217
Crystallographic structures of two bisphosphonate:1-deoxyxylulose-5-phosphate reductoisomerase complexes.	2004 Sep 8	15339150
A fragment-based approach to understanding inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase.	2005 Oct	16116659
Synthesis and biological evaluation of cyclopropyl analogues of fosmidomycin as potent Plasmodium falciparum growth inhibitors.	2006 Apr 20	16610809
An alternative high-performance liquid chromatographic method for determination of clindamycin in plasma.	2006 Jan	16771232
Involvement of 2-C-methyl-D-erythritol-4-phosphate pathway in biosynthesis of aphidicolin-like tetracyclic diterpene of Scoparia dulcis.	2006 May	16651787
Isoprenoid biosynthesis in plants - 2C-methyl-D-erythritol-4-phosphate synthase (IspC protein) of Arabidopsis thaliana.	2006 Oct	16972937
Bioassay for determination of fosmidomycin in plasma and urine: application for pharmacokinetic dose optimisation.	2007 Apr	17258829
gamma-Substituted bis(pivaloyloxymethyl)ester analogues of fosmidomycin and FR900098.	2007 Dec	17994605
Organocatalytic asymmetric direct phosphonylation of alpha,beta-unsaturated aldehydes: mechanism, scope, and application in synthesis.	2007 Nov 9	17927255
The structure of Mycobacteria 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase, an essential enzyme, provides a platform for drug discovery.	2007 Oct 23	17956607
Gateways to clinical trials.	2007 Sep	17982511
Significance of terpenoids in induced indirect plant defence against herbivorous arthropods.	2008 Apr	18208515
Synthesis of beta- and gamma-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates.	2008 Mar 15	18158249

Patents

Sample Use Guides

In Vivo Use Guide

Fosmidomycin-clindamycin (30 mg/kg and 10 mg/kg) given twice daily for three days

Route of Administration: Oral

In Vitro Use Guide

Assay mixtures (total volume: 200 mL) contained 100 mm Tris hydrochloride (pH 7.6), 4 mm MnCl2, 0.5 mm dithiothreitol (DTT), 0.5 mm NADPH, 10–30 nm of recombinant IspC protein (P. falciparum) or 100 mm Tris hydrochloride (pH 8.0), 10 mm MgCl2, 1mm NADPH, 27 nm of recombinant IspC protein (E. coli). Dilution series (1:2) of inhibitor 1 (Fosmidomycin) covered the concentration range of 200 mm to 1 nm. The reaction was started by addition of 1-deoxyxylulose 5-phosphate to a final concentration of 1 mm. The reaction was monitored photometrically (room temperature for P. falciparum or 37C for E. coli) at 340 nm in a microplate reader

Name

Type

Language

FOSMIDOMYCIN

Official Name

English

FOSMIDOMYCIN [MI]

Preferred Name

English

fosmidomycin [INN]

Common Name

English

FOSMIDOMYCIN [MART.]

Common Name

English

(3-(N-HYDROXYFORMAMIDO)PROPYL)PHOSPHONIC ACID

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C258