Dexpramipexole | KNS-760704 | CAS#104632-28-2 | 104632-27-1 | ALS

MedKoo Cat#: 319786 | Name: Dexpramipexole

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Dexpramipexole, also known as KNS-760704, is an orally administered drug candidate shown to selectively and significantly lower eosinophil counts in human blood and tissue. Dexpramipexole is the enantiomer of pramipexole. It is a low molecular weight, orally bioavailable, water-soluble small molecule with linear pharmacokinetics. Dexpramipexole (DPX) easily crosses the blood brain barrier (BBB) and exerts antioxidative properties by reducing ROS production, while the role of DPX in ferroptosis after ICH remains elusive. A 2010 Phase II clinical trial involving 102 patients showed a slowing of ALS disease progression.[5] In January 2013, Biogen Idec announced that it was discontinuing its development of dexpramipexole in ALS due to lack of efficacy in a Phase III study.[1]

Chemical Structure

Dexpramipexole

CAS#104632-28-2 (free base)

Theoretical Analysis

MedKoo Cat#: 319786

Name: Dexpramipexole

CAS#: 104632-28-2 (free base)

Chemical Formula: C10H17N3S

Exact Mass: 211.1143

Molecular Weight: 211.33

Elemental Analysis: C, 56.84; H, 8.11; N, 19.88; S, 15.17

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Related CAS #

104632-27-1 (2HCl) 104632-28-2 (free base) 908244-04-2 (2HCl hydrate)

Synonym

KNS-760704; KNS 760704; KNS760704; (R)-Pramipexole; Dexpramipexole; R-(+)-Pramipexole

IUPAC/Chemical Name

(R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

InChi Key

FASDKYOPVNHBLU-SSDOTTSWSA-N

InChi Code

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

SMILES Code

NC1=NC2=C(C[C@H](NCCC)CC2)S1

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Dexpramipexole (KNS-760704), also known as R-(+)-Pramipexole, is a neuroprotective agent and weak non-ergoline dopamine agonist.

In vitro activity:

It was first asked whether DEX (dexpramipexole) improves energy dynamics of primary cultures of neural cells. Cultures of pure cortical neurons or glia from mice were therefore exposed to the drug and intracellular ATP concentrations measured by different means. It was found that DEX increased ATP content in both types of cultures (Figure 1A, B). These findings suggested that DEX increases energy production in neural cells by promoting mitochondrial ATP production. To confirm this hypothesis, ATP production was next monitored within mitochondria of living neurons or astrocytes by means of a mitochondrially targeted luciferase as sensor of ongoing mitochondrial ATP synthesis. Again, it was found that preincubation with DEX increased photon emission of transfected neurons or astrocytes (Supporting Information Figure S1). Additionally, DEX reduced ATP loss in mixed cortical cell cultures exposed to in vitro ischaemia. The drug also improved energy recovery upon re‐exposure of cultures to nutrients and normoxia (Figure 1E). Consistent with the effects of DEX on mitochondrial bioenergetics, it was found that the drug reduced both the extent of intracellular Ca2+ increase and the number of cells undergoing DCD in cultured primary neurons exposed to OGD (Figure 1F–H). Importantly, in keeping with the causative role of DCD in ischaemic neurodegeneration, DEX reduced cell death of both primary neuronal or glial cultures exposed to OGD (Supporting Information Figure S3). Reference: Br J Pharmacol. 2018 Jan; 175(2): 272–283. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758384/

In vivo activity:

The effects of dexpramipexole on infarct volumes and neurological functions were evaluated in mice following proximal or distal middle cerebral artery occlusion (MCAo). As shown in Figure 4A–C, DEX administered twice daily starting at reperfusion reduced ischaemic brain injury in mice subjected to tMCAo. To confirm the ability of DEX to support mitochondrial bioenergetics, ATP content was anaylzyed within the ischaemic penumbra early (3 h) after reperfusion. Data shown in Figure 4D indicate that energy content of the ischaemic brain tissue was higher in mice treated with DEX. The same dosing was then prolonged up to 7 days and evaluated neuroscore of tMCAo mice for 1 month. Remarkably, DEX provided functional neuroprotection, leading to significant recovery of sensorimotor functions (Figure 4E, F). It was also found that DEX reduced injury of permanent brain ischaemia when treatment started either immediately or even 1 h after artery cauterization (Figure 4L, M). Remarkably, the drug afforded ischaemic neuroprotection even in rats subjected to permanent brain ischaemia (Figure 4N–P), thereby indicating that DEX‐dependent ischaemic neuroprotection in vivo is not species specific. Reference: Br J Pharmacol. 2018 Jan; 175(2): 272–283. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758384/

	Solvent	mg/mL	mM
Solubility
	DMSO	2.1	10.00

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 211.33 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Muzzi M, Gerace E, Buonvicino D, Coppi E, Resta F, Formentini L, Zecchi R, Tigli L, Guasti D, Ferri M, Camaioni E, Masi A, Pellegrini-Giampietro DE, Mannaioni G, Bani D, Pugliese AM, Chiarugi A. Dexpramipexole improves bioenergetics and outcome in experimental stroke. Br J Pharmacol. 2018 Jan;175(2):272-283. doi: 10.1111/bph.13790. Epub 2017 May 12. PMID: 28320070; PMCID: PMC5758384. 2. Buonvicino D, Ranieri G, Pratesi S, Gerace E, Muzzi M, Guasti D, Tofani L, Chiarugi A. Neuroprotection induced by dexpramipexole delays disease progression in a mouse model of progressive multiple sclerosis. Br J Pharmacol. 2020 Jul;177(14):3342-3356. doi: 10.1111/bph.15058. Epub 2020 Apr 18. PMID: 32199028; PMCID: PMC7312322

In vitro protocol:

In vivo protocol:

1. Muzzi M, Gerace E, Buonvicino D, Coppi E, Resta F, Formentini L, Zecchi R, Tigli L, Guasti D, Ferri M, Camaioni E, Masi A, Pellegrini-Giampietro DE, Mannaioni G, Bani D, Pugliese AM, Chiarugi A. Dexpramipexole improves bioenergetics and outcome in experimental stroke. Br J Pharmacol. 2018 Jan;175(2):272-283. doi: 10.1111/bph.13790. Epub 2017 May 12. PMID: 28320070; PMCID: PMC5758384 2. Buonvicino D, Ranieri G, Pratesi S, Gerace E, Muzzi M, Guasti D, Tofani L, Chiarugi A. Neuroprotection induced by dexpramipexole delays disease progression in a mouse model of progressive multiple sclerosis. Br J Pharmacol. 2020 Jul;177(14):3342-3356. doi: 10.1111/bph.15058. Epub 2020 Apr 18. PMID: 32199028; PMCID: PMC7312322.

1: Vieira FG, LaDow E, Moreno A, Kidd JD, Levine B, Thompson K, Gill A, Finkbeiner S, Perrin S. Dexpramipexole is ineffective in two models of ALS related neurodegeneration. PLoS One. 2014 Dec 19;9(12):e91608. doi: 10.1371/journal.pone.0091608. eCollection 2014. PubMed PMID: 25526593; PubMed Central PMCID: PMC4272269. 2: Alavian KN, Dworetzky SI, Bonanni L, Zhang P, Sacchetti S, Li H, Signore AP, Smith PJ, Gribkoff VK, Jonas EA. The mitochondrial complex V-associated large-conductance inner membrane current is regulated by cyclosporine and dexpramipexole. Mol Pharmacol. 2015 Jan;87(1):1-8. doi: 10.1124/mol.114.095661. Epub 2014 Oct 20. PubMed PMID: 25332381; PubMed Central PMCID: PMC4279080. 3: Wei D, Wu C, He P, Kerr D, Stecher S, Yang L. Chiral liquid chromatography-tandem mass spectrometry assay to determine that dexpramipexole is not converted to pramipexole in vivo after administered in humans. J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Nov 15;971:133-40. doi: 10.1016/j.jchromb.2014.09.029. Epub 2014 Sep 30. PubMed PMID: 25289790. 4: Bozik ME, Mitsumoto H, Brooks BR, Rudnicki SA, Moore DH, Zhang B, Ludolph A, Cudkowicz ME, van den Berg LH, Mather J, Petzinger T Jr, Archibald D. A post hoc analysis of subgroup outcomes and creatinine in the phase III clinical trial (EMPOWER) of dexpramipexole in ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Sep;15(5-6):406-13. doi: 10.3109/21678421.2014.943672. Epub 2014 Aug 15. PubMed PMID: 25125035. 5: He P, Kerr D, Marbury T, Ries D, Farwell W, Stecher S, Dong Y, Wei D, Rogge M. Pharmacokinetics of renally excreted drug dexpramipexole in subjects with impaired renal function. J Clin Pharmacol. 2014 Dec;54(12):1383-90. doi: 10.1002/jcph.353. Epub 2014 Jul 3. PubMed PMID: 24965504; PubMed Central PMCID: PMC4241030. 6: Cudkowicz ME, van den Berg LH, Shefner JM, Mitsumoto H, Mora JS, Ludolph A, Hardiman O, Bozik ME, Ingersoll EW, Archibald D, Meyers AL, Dong Y, Farwell WR, Kerr DA; EMPOWER investigators. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol. 2013 Nov;12(11):1059-67. doi: 10.1016/S1474-4422(13)70221-7. Epub 2013 Sep 23. Erratum in: Lancet Neurol. 2013 Nov;12(11):1042. Carbonell, J G [corrected to Gamez, J]. PubMed PMID: 24067398. 7: Rudnicki SA, Berry JD, Ingersoll E, Archibald D, Cudkowicz ME, Kerr DA, Dong Y. Dexpramipexole effects on functional decline and survival in subjects with amyotrophic lateral sclerosis in a Phase II study: subgroup analysis of demographic and clinical characteristics. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan;14(1):44-51. doi: 10.3109/17482968.2012.723723. Epub 2012 Sep 17. PubMed PMID: 22985432. 8: Corcia P, Gordon PH. Amyotrophic lateral sclerosis and the clinical potential of dexpramipexole. Ther Clin Risk Manag. 2012;8:359-66. doi: 10.2147/TCRM.S21981. Epub 2012 Aug 27. PubMed PMID: 22956874; PubMed Central PMCID: PMC3431958. 9: Alavian KN, Dworetzky SI, Bonanni L, Zhang P, Sacchetti S, Mariggio MA, Onofrj M, Thomas A, Li H, Mangold JE, Signore AP, Demarco U, Demady DR, Nabili P, Lazrove E, Smith PJ, Gribkoff VK, Jonas EA. Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency. Brain Res. 2012 Mar 29;1446:1-11. doi: 10.1016/j.brainres.2012.01.046. Epub 2012 Jan 28. PubMed PMID: 22364637; PubMed Central PMCID: PMC3746080. 10: Cudkowicz M, Bozik ME, Ingersoll EW, Miller R, Mitsumoto H, Shefner J, Moore DH, Schoenfeld D, Mather JL, Archibald D, Sullivan M, Amburgey C, Moritz J, Gribkoff VK. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med. 2011 Nov 20;17(12):1652-6. doi: 10.1038/nm.2579. PubMed PMID: 22101764. 11: Cheah BC, Kiernan MC. Dexpramipexole, the R(+) enantiomer of pramipexole, for the potential treatment of amyotrophic lateral sclerosis. IDrugs. 2010 Dec;13(12):911-20. Review. PubMed PMID: 21154151. 12: Bozik ME, Mather JL, Kramer WG, Gribkoff VK, Ingersoll EW. Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects. J Clin Pharmacol. 2011 Aug;51(8):1177-85. doi: 10.1177/0091270010379412. Epub 2010 Oct 19. PubMed PMID: 20959524.