DEXPRAMIPEXOLE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C10H17N3S
Molecular Weight	211.327
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCCN[C@@H]1CCC2=C(C1)SC(N)=N2

InChI

InChIKey=FASDKYOPVNHBLU-SSDOTTSWSA-N

InChI=1S/C10H17N3S/c1-2-5-12-7-3-4-8-9(6-7)14-10(11)13-8/h7,12H,2-6H2,1H3,(H2,11,13)/t7-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C10H17N3S
Molecular Weight	211.327
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.xconomy.com/boston/2013/01/03/biogen-idecs-als-drug-fails-phase-iii-trial/ | https://www.ncbi.nlm.nih.gov/pubmed/28320070 | https://www.ncbi.nlm.nih.gov/pubmed/25332381

Dexpramipexole (also known as KNS-760704/R-pramipexole) was originally developed by University of Virginia researchers to treat Amyotrophic Lateral Sclerosis and then was licensed to global biotechnology company Biogen Idec for further development. However, on phase III clinical trial the study of this drug was discontinued. Biogen said the drug neither slowed the loss of muscle function nor prolonged the lives of patients with ALS, often called Lou Gehrig’s disease. Nor did it show any efficacy in secondary endpoints of the clinical trial, or work in any sub-group of patients—about a big a failure as a company could have a Phase III trial. In addition, was discovered, that dexpramipexole was able to bind to beta-subunit of the mitochondrial F1/FO ATP synthase complex and increased its activity, thus reduced ischemic brain injury. These findings, together with the excellent brain penetration and favorable safety profile in humans, make dexpramipexole a drug with realistic translational potential for the treatment of stroke.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
ATP synthase subunit beta, mitochondrial 19 Target ID: P10719 Gene ID: 171374.0 Gene Symbol: Atp5b Target Organism: Rattus norvegicus (Rat) Sources: https://www.ncbi.nlm.nih.gov/pubmed/28320070	Binding Agent 1037

Conditions

Condition	Modality	Targets	Highest Phase	Product
Amyotrophic lateral sclerosis 41 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25526593	Primary		Phase III 651	Unknown Approved Use Unknown
Stroke 143 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28320070	Primary		Not Provided 505	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
479 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20959524	150 mg 2 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DEXPRAMIPEXOLE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
781 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20959524	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		DEXPRAMIPEXOLE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
3749 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20959524	150 mg 2 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DEXPRAMIPEXOLE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
8624 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20959524	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		DEXPRAMIPEXOLE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
8.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20959524	150 mg 2 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:		DEXPRAMIPEXOLE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
6.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20959524	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		DEXPRAMIPEXOLE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
150 mg 2 times / day multiple, oral (total daily dose) Highest studied dose Dose: 150 mg, 2 times / day Route: oral Route: multiple Dose: 150 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/22101764/	unhealthy n = 44 Health Status: unhealthy Condition: amyotrophic lateral sclerosis Sex: M+F Food Status: UNKNOWN Population Size: 44 Sources: https://pubmed.ncbi.nlm.nih.gov/22101764/	Other AEs: Upper respiratory tract infection, Anxiety... Other AEs: Upper respiratory tract infection (7%) Anxiety (11%) Muscular weakness (16%) Sinusitis (11%) Cough (11%) Constipation (25%) Insomnia (14%) Muscle spasticity (2%) Salivary hypersecretion (11%) Depression (11%) Dyspnea (14%) Dysarthria (11%) Dysphagia (9%) Fall (25%) Headache (14%) Dry mouth (16%) Oedema peripheral (2%) Sources: https://pubmed.ncbi.nlm.nih.gov/22101764/

AEs

PubMed

Title	Date	PubMed
Increased risk of somnolence with the new dopamine agonists in patients with Parkinson's disease: a meta-analysis of randomised controlled trials.	2001	11665873
Antiparkinsonian drugs and "sleep attacks".	2001 Apr 3	11314438
Efficacy and tolerability of dopamine agonists in a parkinsonian population.	2001 Feb	11487183
Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series.	2001 Jul	11518474
Modafinil and pramipexole-associated somnolence.	2001 Jul	11481716
Neuroprotective effects of pramipexole in young and aged MPTP-treated mice.	2001 Jun 29	11423078
Pramipexole augmentation in panic with agoraphobia.	2001 Mar	11230001
Locomotor hypoactivity and motor disturbances--behavioral effects induced by intracerebellar microinjections of dopaminergic DA-D2/D3 receptor agonists.	2001 Sep-Oct	11990070
DA agonists -- non-ergot derivatives: pramipexole: management of Parkinson's disease.	2002	12211148
[Pramipexole in Parkinson disease. Results of a treatment observation].	2002 Aug	12242961
Acute placebo-controlled sleep laboratory studies and clinical follow-up with pramipexole in restless legs syndrome.	2002 Aug	12242580
[The usefulness of dopaminergic drugs in traumatic brain injury].	2002 Aug 16-31	12235569
[Rhabdomyolysis as a complication of Parkinson's disease].	2002 Jan-Feb	12165940
The effects of speech therapy and pharmacological treatments on voice and speech in Parkinson s disease: a review of the literature.	2002 Jul	12132992
Gateways to clinical trials.	2002 Jul-Aug	12224444
Pramipexole in patients with Parkinson's disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study.	2002 Jun	12023411
A case of Parkinsonism due to lithium intoxication: treatment with Pramipexole.	2002 May	12093142
Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics.	2002 May 14	12011296
[Dopamine agonist is effective in Parkinson disease not only against tremor. Depression is also improved].	2002 May 6	12070869
Do dopamine agonists or levodopa modify Parkinson's disease progression?	2002 Nov	12464117
Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens.	2002 Oct	12208558
Pramipexole in Parkinson's disease. A short-term study using the combined levodopa-dopamine agonist test.	2002 Oct-Dec	12675263
Pramipexole in comparison to l-dopa: a neuropsychological study.	2003 Apr	12658365
Pramipexole increases vesicular dopamine uptake: implications for treatment of Parkinson's neurodegeneration.	2003 Aug 8	12921866
Efficacy, safety, and tolerability of pramipexole in untreated and levodopa-treated patients with Parkinson's disease.	2003 Dec 15	14607306
REAL and CALM: what have we learned?	2003 Jul	12815670
The use of dopamine enhancing medications with children in low response states following brain injury.	2003 Jun	12745705
The initial drug treatment of older patients with Parkinson's disease - consider an agonist, but don't demonise dopa.	2003 May	12720606
Randomized, double-blind, 3-month parallel study of the effects of pramipexole, pergolide, and placebo on Parkinsonian tremor.	2003 Nov	14639675
Neuroprotective effects of the novel D3/D2 receptor agonist and antiparkinson agent, S32504, in vitro against 1-methyl-4-phenylpyridinium (MPP+) and in vivo against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a comparison to ropinirole.	2003 Nov	14637109
Oral anticoagulation for ECG tremor artefact simulating atrial fibrillation.	2003 Oct	14609309
Slowing Parkinson's disease progression: recent dopamine agonist trials.	2004 Jan 27	14750218
Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial.	2004 Jul	15262734
Restless legs symptoms in a patient with above knee amputations: a case of phantom restless legs.	2004 Mar-Apr	15252270

Patents

Sample Use Guides

In Vivo Use Guide

Oral tablet 150 mg twice daily for up to 18 months

Route of Administration: Oral

In Vitro Use Guide

It was found that dexpramipexole (DEX) binds to the oligomycin sensitivity–conferring protein (OSCP) and b-subunits of the F1/FO ATP synthase, suggesting that it may indirectly inhibit the c-subunit (mPTP) pore by producing a conformational change in complex V that places F1 over the pore, inhibiting its conductance. The human open reading frame constructs for α, β, b, c, δ, d, ε, γ, and oligomycin sensitivity–conferring protein (OSCP) ATP synthase subunits were used. 293T cells were transfected with the above constructs. On day 3 post-transfection, the cells were lysed. The proteins were eluted from a portion of the samples, and the presence of the proteins on the beads was verified by immunoblot analysis, using mouse anti-Myc antibodies. The protein-bound beads were incubated in the presence of [14C]DEX (range of concentration was: 1-10 uM).

Substance Class	Chemical Created by `admin` on `Sun Dec 18 21:05:44 UTC 2022` Edited by `admin` on `Sun Dec 18 21:05:44 UTC 2022`
Record UNII	WI638GUS96
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

DEXPRAMIPEXOLE

Official Name

English

R-(+)-PRAMIPEXOLE

Common Name

English

2,6-BENZOTHIAZOLEDIAMINE, 4,5,6,7-TETRAHYDRO-N6-PROPYL-, (R)-

Systematic Name

English

DEXPRAMIPEXOLE [USAN]

Common Name

English

(6R)-N6-PROPYL-4,5,6,7-TETRAHYDRO-1,3-BENZOTHIAZOLE-2,6-DIAMINE

Systematic Name

English

2,6-BENZOTHIAZOLEDIAMINE, 4,5,6,7-TETRAHYDRO-N6-PROPYL-, (6R)-

Systematic Name

English

dexpramipexole [INN]

Common Name

English

(R)-PRAMIPEXOLE

Common Name

English

Dexpramipexole [WHO-DD]

Common Name

English

(R)-4,5,6,7-TETRAHYDRO-6-(PROPYLAMINO)-BENZOTHIAZOLE-2-AMINE

Systematic Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

681319