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The Science

PBT434 is the first of a new generation of small molecules from the quinazolinone class of drugs that was specifically designed to block the accumulation and aggregation of alpha-synuclein. Alpha-synuclein is an abundant brain protein widely believed to be involved in the pathogenesis of Parkinson’s disease and certain types of atypical parkinsonism such as Multiple System Atrophy or Dementia with Lewy Bodies.

PBT434 is the first of a new generation of small molecules from the quinazolinone class of drugs that was specifically designed to block the accumulation and aggregation of alpha-synuclein. Alpha-synuclein is of great interest because aggregated forms of the protein are considered a pathological hallmark of Parkinsonian conditions and are a recognised therapeutic target by neuroscientists and clinicians.

PBT434 has been shown in preclinical models to block alpha-synuclein accumulation and to prevent the loss of neurons in the region of the brain primarily affected in Parkinson’s disease, called the substantia nigra. This was demonstrated in several Parkinson’s disease animal models, including tests in transgenic mice that produce excessive amounts of the alpha-synuclein protein. “Finkelstein, et al. Acta Neuropathol Commun 2017; 5: 53.”

Experiments in an animal model of Multiple System Atrophy have also demonstrated the robust efficacy of PBT434. This animal model reproduces the key pathology of human Multiple System Atrophy – abundant clumps of alpha-synuclein inside oligodendroglial cells referred to as “glial cell inclusions”. Oligodendroglial cells have a vital support function in the brain to protect and nourish neurons. In addition, they scavenge abnormal alpha-synuclein released from diseased neurons. PBT434 was shown to reduce both oligomeric and aggregated forms of alpha-synuclein and prevent alpha-synuclein accumulation in affected oligodendroglial cells. Importantly, the beneficial effect on alpha-synuclein led to the preservation of neurons and improved motor function of treated animals.

Increased labile iron has been implicated in the pathology of alpha-synuclein related diseases, such as Parkinson’s disease and Multiple system atrophy (Oakley, et al. Neurology 2007;68:1820–1825. Berg and Youdim. Top Magn Reson Imaging 2006;17;5-17. Kaindlstorfer et al. Journal of Alzheimer’s Disease 61 (2018) 1253–1273). A novel approach for treating these diseases is to reduce labile iron that is causing iron-mediated accumulation and aggregation of α-synuclein, thereby preserving neurons and improving function (Crielaard et al., Nat Rev Drug Discov. 2017 Jun; 16 (2):400-423. Elkouzi et al. Nature Reviews Neurology 2019; 15: 204–223.). PBT434 is thought to act by binding and redistributing labile iron in this manner, but to not interfere with normal, tightly bound iron involved in oxygen transport, energy production and enzyme activity. Benefits of binding labile iron include reducing pathological protein accumulation and its sequelae as well as silencing processes that lead to oxidative stress.

Published Scientific Research

2017
Acta Neuropathologica Communications Neuroscience of Disease
Title: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease. The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease.

https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0456-2 

2018
International Congress of Parkinson’s Disease and Movement Disorders®
Title: PBT434 prevents the accumulation of glial cell inclusions and insoluble alpha‐synuclein in a mouse model of Multiple System Atrophy.

Drug discovery program

Key to maintaining a competitive advantage in the field is the ability for continuous improvement and innovation in the discovery of novel product candidates. The Alterity research team is evaluating new chemical scaffolds that offer mechanisms of action to intercede in disease processes. Using structure-activity relationship insights that have been developed over years of testing and validation by Alterity scientists, innovative patentable chemical compounds are being generated. These compounds are initially screened for activity in biological systems relevant to candidate diseases we are targeting. New screens are being investigated that will assess the ability of a compound to intercede in the pathogenic steps thought to underlie the target disease process, such as protein aggregation and hyperphosphorylation as well as downstream activities such as oxidative stress and cell death. Promising candidates arising from the Translational Research program will be progressed in relevant animal models of Parkinsonian diseases, Alzheimer’s disease or other neurodegenerative diseases.

Patent portfolio

Patent


Status


Invention


“8-Hydroxyquinoline Derivatives”

Filed: July 16, 2003
Applicant: Prana Biotechnology Limited

Patents in Europe, the USA, New Zealand, Canada, Japan, Russia, Singapore, South Korea, Australia, Israel, China, Mexico and South Africa have been Granted. A patent in Hong Kong has been registered.

The invention is directed to chemical scaffolds of the 8-Hydroxyquinoline MPAC class and their utility in the treatment of neurological conditions.

“Neurologically-Active Compounds”

Filed: October 3 , 2003
Applicant: Prana Biotechnology Limited

Patents in the USA, New Zealand, Canada, Japan, Mexico, India, Australia, China, South Korea, Japan, Israel, South Africa and Singapore have been Granted. A case has been Granted in Europe and has been validated in separate countries. A patent in Hong Kong has been registered.

The invention is directed to alternative MPAC chemical structures and their utility in the treatment of neurological conditions.

“Neurologically- Active Compounds”

Filed: April 1, 2005
Applicant: Prana Biotechnology Limited

Patents have been Granted in Singapore, Japan, Mexico, Russia, Australia, the USA, China, Canada, Europe, India, South Korea, Israel, New Zealand and South Africa. A case has been Granted in Europe and has been validated in separate countries. A patent in Hong Kong has been registered.

The invention is directed to ‘F4’ MPAC chemical structures and their utility in the treatment of neurological conditions and includes Parkinson’s disease lead compounds.

“A method of prophylaxis or treatment and agents for same”

Filed: June 22, 2007
Applicant: Prana Biotechnology Limited

A patent has been Granted in the USA, China, Australia, Canada and Japan. A case has been Granted in Europe and has been validated in separate countries.

This invention is directed to novel MPAC compounds and compounds for treating certain brain cancers.

“Quinazolinone compounds”

Filed: 24 December 2008
Applicant: Prana Biotechnology Limited

Patents have been Granted in Japan, Australia, Europe and the USA.

This invention is directed to novel MPAC compounds and to select MPAC’s used in the treatment of Parkinson’s disease. Particularly new 2, 3 substituted F4 compounds.

“4H-Pyrido(1,2-a) Pyrimidin-4-one compounds”

Filed: 2 December 2014 (prov)
Applicant: Prana Biotechnology Limited

PCT National phase patent applications has been filed in Australia, Brazil, Canada, China, EA, EU, India, Japan, Malaysia, NZ, Korea and the USA.

This invention is directed to novel MPAC compounds for the treatment of neurodegenerative diseases. Particularly new ‘F3’ compounds.

“Method of treating immunoglobulin light chain amyloidosis”

Filed: 1 July 2016
Applicant: Prana Biotechnology Limited

A PCT patent application has been filed.

This invention is directed to the treatment of light chain amyloidosis with a known compound.

“A method of the production of 2-substituted-3H-quinazolin-4-ones-I”

Filed: 12 March 2017
Applicant: Prana Biotechnology Limited

An Australian provisional application has been refiled.

This invention is directed to synthetic routes for quinazolinone compounds.

“A method of the production of 2-substituted-3H-quinazolin-4-ones-II”

Filed: 12 March 2017
Applicant: Prana Biotechnology Limited

An Australian provisional application has been refiled.

This invention is directed to synthetic routes for quinazolinone compounds.

“Processes for the preparation of 8-Hydroxy quinoline Derivatives”

Filed: 4 January 2017
Applicant: Prana Biotechnology Limited

An Australian provisional application has been refiled.

This invention is directed to synthetic routes for 8-Hydroxyquinoline Derivatives.

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