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

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 1064

Conditions

Condition	Modality	Targets	Highest Phase	Product
Amyotrophic lateral sclerosis 41 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25526593	Primary		Phase III 656	Unknown Approved Use Unknown
Stroke 144 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28320070	Primary		Not Provided 504	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
Are dopamine receptor agonists neuroprotective in Parkinson's disease?	2001	11419913
Antiparkinsonian drugs and "sleep attacks".	2001 Apr 3	11314438
Influence of L-dopa and pramipexole on striatal dopamine transporter in early PD.	2001 Jun 12	11402115
Neuroprotective effects of pramipexole in young and aged MPTP-treated mice.	2001 Jun 29	11423078
Newer dopamine agonists in the treatment of restless legs syndrome.	2001 May	11346069
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
Gateways to Clinical Trials.	2002 Apr	12087878
[The usefulness of dopaminergic drugs in traumatic brain injury].	2002 Aug 16-31	12235569
Gateways to clinical trials.	2002 Jul-Aug	12224444
Influence of sildenafil on copulatory behaviour in sluggish or normal ejaculator male rats: a central dopamine mediated effect?	2002 Mar	11955526
A case of Parkinsonism due to lithium intoxication: treatment with Pramipexole.	2002 May	12093142
[Dopamine agonist is effective in Parkinson disease not only against tremor. Depression is also improved].	2002 May 6	12070869
Combination of two different dopamine agonists in the management of Parkinson's disease.	2002 Sep	12548370
Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson's disease: a meta-analysis.	2003	12688834
Fibromyalgia and pramipexole: promise and precaution.	2003 Dec	14719231
Pramipexole in Restless Legs syndrome. Evaluation by suggested immobilization test.	2003 Dec	14673586
Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study.	2003 Jul	12823492
REAL and CALM: what have we learned?	2003 Jul	12815670
[(123)I]beta-CIT SPECT is a useful method for monitoring dopaminergic degeneration in early stage Parkinson's disease.	2003 Mar	12588911
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
Pramipexole in the management of restless legs syndrome: an extended study.	2003 Nov 1	14655914
The effects of pramipexole in REM sleep behavior disorder.	2003 Nov 25	14638967
The effects of dopamine D3 agonists and antagonists in a nonhuman primate model of tardive dyskinesia.	2004 Aug	15301939
Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial.	2004 Jul	15262734
Pramipexole for bipolar II depression: a placebo-controlled proof of concept study.	2004 Jul 1	15219473
Conversion from dopamine agonists to pramipexole. An open-label trial in 227 patients with advanced Parkinson's disease.	2004 Mar	15015015
Pramipexole for the treatment of uremic restless legs in patients undergoing hemodialysis.	2004 Mar 9	15007148
Restless legs symptoms in a patient with above knee amputations: a case of phantom restless legs.	2004 Mar-Apr	15252270
Pramipexole v. levodopa as initial treatment for Parkinson's disease: a randomized clinical-economic trial.	2004 Sep-Oct	15358996

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).

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