Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C9H11NO5 |
Molecular Weight | 213.1873 |
Optical Activity | ( - ) |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
N[C@@H]([C@H](O)C1=CC(O)=C(O)C=C1)C(O)=O
InChI
InChIKey=QXWYKJLNLSIPIN-JGVFFNPUSA-N
InChI=1S/C9H11NO5/c10-7(9(14)15)8(13)4-1-2-5(11)6(12)3-4/h1-3,7-8,11-13H,10H2,(H,14,15)/t7-,8+/m0/s1
Molecular Formula | C9H11NO5 |
Molecular Weight | 213.1873 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
DescriptionSources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/007513Orig1s024lbl.pdfhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203202lbl.pdfCurator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/?term=17214596; http://www.ncbi.nlm.nih.gov/pubmed/?term=18368304
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/007513Orig1s024lbl.pdfhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203202lbl.pdf
Curator's Comment: description was created based on several sources, including http://www.ncbi.nlm.nih.gov/pubmed/?term=17214596; http://www.ncbi.nlm.nih.gov/pubmed/?term=18368304
Droxidopa (Northera, Chelsea Therapeutics) is a synthetic catecholamino acid precursor of norepinephrine indicated for the treatment of orthostatic dizziness or lightheadedness in adult patients with symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Droxidopa was approved as oral therapy in February 2014 under the FDA’s accelerated approval program. Droxidopa is directly metabolized to norepinephrine by dopadecarboxylase. The specific mechanism of action of the drug is not known completely, but it is supposed to exert the pharmacological effects through norepinephrine and not through the parent molecule or other metabolites. It increases blood flow to the brain by stimulating peripheral arterial and venous vasoconstriction.
CNS Activity
Sources: http://www.caam.rice.edu/~cox/wrap/norepinephrine.pdfhttp://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM292631.pdf
Curator's Comment: Droxidopa, a prodrug, is converted mostly peripherally, but also centrally (as it passes through the blood brain barrier) into norepinephrine (NE).
Originator
Sources: Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales (1932), 111, 884-6.http://www.businesswire.com/news/home/20140218006891/en/Chelsea-Therapeutics-Announces-FDA-Accelerated-Approval-NORTHERA%E2%84%A2
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2094118 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6124637 |
2600.0 nM [EC50] | ||
Target ID: CHEMBL229 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26125514 |
9.1 nM [EC50] | ||
Target ID: CHEMBL1867 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25282262 |
128.8 nM [EC50] | ||
Target ID: CHEMBL1942 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18578476 |
61.7 nM [EC50] | ||
Target ID: CHEMBL1916 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18578476 |
794.3 nM [EC50] | ||
Target ID: CHEMBL2331074 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | LEVOPHED Approved UseINDICATIONS: Temporary relief of sleep, emotional, nervous or memory disorders. Launch Date1950 |
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Primary | LEVOPHED Approved UseINDICATIONS: Temporary relief of sleep, emotional, nervous or memory disorders. Launch Date1950 |
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Primary | LEVOPHED Approved UseINDICATIONS: Temporary relief of sleep, emotional, nervous or memory disorders. Launch Date1950 |
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Primary | NORTHERA Approved UseIndicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure [Parkinson's disease (PD), multiple system atrophy and pure autonomic failure], dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Launch Date2014 |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2.4 min |
unknown, intravenous |
NOREPINEPHRINE unknown | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
75% |
unknown, intravenous |
NOREPINEPHRINE unknown | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
0.6 ug/kg/min single, intravenous Highest studied dose Dose: 0.6 ug/kg/min Route: intravenous Route: single Dose: 0.6 ug/kg/min Sources: |
unhealthy, mean 65.5 years n = 85 Health Status: unhealthy Condition: cardiogenic shock Age Group: mean 65.5 years Sex: M+F Population Size: 85 Sources: |
Other AEs: Mean arterial pressure high... |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Mean arterial pressure high | 7.2% | 0.6 ug/kg/min single, intravenous Highest studied dose Dose: 0.6 ug/kg/min Route: intravenous Route: single Dose: 0.6 ug/kg/min Sources: |
unhealthy, mean 65.5 years n = 85 Health Status: unhealthy Condition: cardiogenic shock Age Group: mean 65.5 years Sex: M+F Population Size: 85 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/9848110/ Page: - |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/9848110/ Page: - |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/9848110/ Page: - |
no |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: - |
yes [Km 10.65 uM] | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/9687576/ Page: - |
yes [Km 1900 uM] | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/26432838/ Page: - |
yes | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/27355037/ Page: - |
yes |
PubMed
Title | Date | PubMed |
---|---|---|
Microphysiometric analysis of human alpha1a-adrenoceptor expressed in Chinese hamster ovary cells. | 1999 Jun |
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Nitroprusside inhibits thermal hyperalgesia induced by noradrenaline in capsaicin-treated skin. | 1999 Mar |
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[Distributive shock and it's therapy by cardio-vascular acting drugs]. | 1999 Oct |
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Characterization of human recombinant alpha(2A)-adrenoceptors expressed in Chinese hamster lung cells using intracellular Ca(2+) changes: evidence for cross-talk between recombinant alpha(2A)- and native alpha(1)-adrenoceptors. | 2000 Apr |
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Effect of dexmedetomidine on the release of [3H]-noradrenaline from rat kidney cortex slices: characterization of alpha2-adrenoceptor. | 2001 Apr |
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Plasma catecholamine and cardiovascular responses to physostigmine in Alzheimer's disease and aging. | 2001 Feb |
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alpha(1B) adrenergic receptors in gonadotrophin-releasing hormone neurones: relation to Transport-P. | 2001 Jan |
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Beta-adrenoceptor stimulation attenuates the hypertrophic effect of alpha-adrenoceptor stimulation in adult rat ventricular cardiomyocytes. | 2001 Jan |
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Ambulatory norepinephrine treatment of severe autonomic orthostatic hypotension. | 2001 Jan |
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Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest. | 2001 Jan |
|
Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. | 2001 Jan |
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Catecholaminergic regulation of Na-K-Cl cotransport in pigmented ciliary epithelium: differences between PE and NPE. | 2001 Jan |
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The antidepressant-sensitive dopamine transporter in Drosophila melanogaster: a primordial carrier for catecholamines. | 2001 Jan |
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Chronic type IV phosphodiesterase inhibition protects glomerular filtration rate and renal and mesenteric blood flow in a zymosan-induced model of multiple organ dysfunction syndrome treated with norepinephrine. | 2001 Jan |
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Melatonin potentiates NE-induced vasoconstriction without augmenting cytosolic calcium concentration. | 2001 Jan |
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Increased alpha(1)- and alpha(2)-adrenoceptor-mediated contractile responses of human skeletal muscle resistance arteries in chronic limb ischemia. | 2001 Jan |
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Chromaffin-adrenocortical cell interactions: effects of chromaffin cell activation in adrenal cell cocultures. | 2001 Jan |
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Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. | 2001 Jan 1 |
|
Nitric oxide synthase activity in peripheral polymorphonuclear leukocytes in patients with chronic congestive heart failure. | 2001 Jan 15 |
|
Determination of residues in the norepinephrine transporter that are critical for tricyclic antidepressant affinity. | 2001 Mar 16 |
Patents
Sample Use Guides
Acute Hypotension. Initial: 8-12 mcg/min IV infusion; titrate to effect; Maintenance: 2-4 mcg/min IV infusion
Cardiac Arrest. Initial: 8-12 mcg/min IV infusion; titrate to effect; Maintenance: 2-4 mcg/min IV infusion
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27650061
Human umbilical vein endothelial cell line (ECV-304, Shanghai Institute of Cell Biology, Chinese Academy of Science) were used for activity evaluation. Cells were conventionally cultured with modified alpha-MEM containing 10% fetal bovine serum Before all the manipulation experiments, the ECV-304 (VECs) were shifted to serum-free medium (normal medium) and then divided into three groups as follows. Control group was cultured in normal medium in which 0 mol/L NE (Norepinephrine) was detecteded using the NE ELISA kit. NE+Inhibitor group was cultured in normal medium added with 10^-7 mol/L NE (Harcest Pharmaceutical CO,. Shanghai, China) and NE blocker Amitriptyline hydrochloride (10-6 mol/L). NE+Isotype group was cultured in normal medium added with 10^-7 mol/L NE (Norepinephrine) and a negative isotype of NE blocker Amitriptyline hydrochloride. The dose of NE utilized in the experiments was determined in advance through titration. It was selected to approximate the normal concentration in vivo. After 24 h of culture, the supernatant from each group was collected to measure SDF-1 using an ELISA kit (Human CXCL12/SDF-1 alpha Quantikine ELISA Kit; R&D Systems, USA) according to the manufacturer’s protocol. Similarly, the cells from the cell culture were collected for Western blotting analysis. First, proteins were extracted from the cells using the M-PER mammalian protein extraction reagent (Thermo Fisher Scientific, Hudson, USA). Then, the proteins were resolved on a NuPAGE gel and transferred to nylon membranes. After blocking with 7% fat-free dry milk for 2 h, the membranes were incubated with polyclonal rabbit anti-human SDF-1, JNK or p-JNK antibodies (1:200; Santa Cruz) at 4C overnight. After incubation with horseradish peroxidase-conjugated IgG (Santa Cruz) for 1 h, the membranes were treated with chemiluminescent substrate (Thermo) to visualize the protein bands.
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 17:01:18 GMT 2023
by
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on
Sat Dec 16 17:01:18 GMT 2023
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Record UNII |
J7A92W69L7
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Record Status |
Validated (UNII)
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Record Version |
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
229506
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EU-Orphan Drug |
EU/3/07/465
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WHO-ATC |
C01CA27
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EU-Orphan Drug |
EU/3/07/466
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NCI_THESAURUS |
C38149
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UU-114
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971
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J7A92W69L7
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L-DOPS
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D015103
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60568
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C73266
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1489913
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100000081029
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DTXSID6046422
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N0000178478
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PRIMARY | Increased Blood Pressure [PE] | ||
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23651-95-8
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7391
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J7A92W69L7
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CHEMBL2103827
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92974
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DB06262
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SUB06420MIG
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m4774
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PRIMARY | Merck Index | ||
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6120
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31524
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Related Record | Type | Details | ||
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TARGET -> AGONIST |
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TARGET -> AGONIST |
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TARGET -> AGONIST |
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BINDER->LIGAND |
BINDING
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TARGET -> AGONIST |
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METABOLIC ENZYME -> SUBSTRATE |
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RACEMATE -> ENANTIOMER |
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METABOLIC ENZYME -> SUBSTRATE |
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TARGET -> INHIBITOR |
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TARGET -> INHIBITOR |
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TARGET -> AGONIST |
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TARGET -> AGONIST |
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TARGET -> AGONIST |
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Related Record | Type | Details | ||
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
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METABOLITE -> PARENT |
MAJOR
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METABOLITE -> PARENT |
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METABOLITE ACTIVE -> PRODRUG |
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IMPURITY -> PARENT |
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IMPURITY -> PARENT |
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ACTIVE MOIETY |
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Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Volume of Distribution | PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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Biological Half-life | PHARMACOKINETIC |
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