CeNeS and Tripos advances COMT research

Related tags Dopamine

CeNeS Pharmaceuticals and Tripos have entered into a new agreement
to continue their collaboration on COMT inhibitors, which represent
a new breed of therapy for Parkinson's disease and other psychotic
disorders such as schizophrenia.

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease. It affects approximately 2 per cent of the population over the age of 65, representing approximately 4 million patients worldwide.

The collaboration is an extension of an original agreement between the two companies that commenced in 2003. This research programme resulted in the identification of several series of novel compounds active against the target catechol-O-methyltransferase (COMT).

COMT inhibitors are currently used clinically for adjunct therapy in Parkinson's disease since they prolong the effects of the dopamine precursor L-DOPA. CeNeS began work to improve on current drugs in 2002 and has been working with Tripos to design novel COMT inhibitors that may improve on existing treatments.

Under the terms of the agreement, Tripos, a provider of drug discovery chemistry and informatics solutions, has been concentrating on lead identification, follow-up and chemical optimisation of candidate molecules. Financial terms of the agreement were not disclosed.

Tripos uses CeNeS'​ proprietary information and internal chemical design platform along with its structure-based design tools to investigate the interaction of proposed leads with the validated target. Novel compounds have been selected for synthesis and screened for biological activity. The new project will involve the optimisation of these active compounds.

News of this collaboration comes after new research, published in Biological Psychiatry, revealed that one in four people carries genes that increases vulnerability to psychotic illnesses if he or she smokes cannabis as a teenager.

The increased risk applies to people who inherit variants of COMT who also smoked cannabis as teenagers. The study suggested about a quarter of the population have this genetic make-up, and up to 15 per cent of the group are likely to develop psychotic conditions if exposed to the drug early in life.

Dr Avshalom Caspi, one of the led researchers of this study, said the valine gene variant and cannabis affect the brain's dopamine system in similar fashion, suggesting that they deliver a "double dose" that can be damaging.

Caspi said that the work needed to be replicated by others to confirm the findings. He added that it was also possible that the gene involved was not COMT but a neighbour.

COMT is known to play a part in the production of dopamine, a brain-signalling chemical that is abnormal in schizophrenia. It comes in two variants, known as valine or methionine, and every person has two copies, one from each parent.

"CeNeS' strategy is to develop novel products that reduce the risks inherent in drug development by focusing on known mechanisms and established clinical targets. Two COMT inhibitors are marketed currently. One does not enter the brain effectively and the other is associated with serious liver toxicity. Our goal is to identify compounds without these deficits,"​ said Neil Clark, CeNeS chief executive officer.

Novartis' entacapone (Comtan) and Roche's Tolcapone (Tasmar) and are the two well-established COMT inhibitors. Whilst effective, they both suffer from side effects that include dyskinesias, hallucinations, diarrhea, hypotension and urine discoloration. With tolcapone, liver toxicity is also a possible side effect, limiting its use.

Parkinson's disease results from a loss of the neurotransmitter dopamine in the brain. Replacement therapy using L-DOPA, the precursor of dopamine, is the main treatment for Parkinson's disease.

However, L-DOPA is quickly metabolised in the gut and liver allowing only a small proportion (approximately one per cent) to reach the brain. Therefore, L-DOPA is formulated with agents that inhibit the breakdown of L-DOPA by DOPA-decarboxylase, such as carbidopa and benserazide.

After prolonged use, the beneficial effects of L-DOPA become reduced and patients develop motor fluctuations and dyskinesias. These probably represent the biggest single problem in the long-term management of a patient with Parkinson's disease.

The enzyme catechol-O-methyl transferase ("COMT") also causes significant depletion of L-DOPA in the brain and periphery, limiting the efficacy of L-DOPA replacement therapy.

The global market for drugs targeting Parkinson's disease was $1.7 billion (€1.3 billion) in 2003 and is forecast to grow substantially over the next decade with an increased prevalence of the disease as a consequence of the ageing population.

COMT inhibitors currently have a 10 per cent share of the Parkinson's disease market by value and their usage is growing. Treatments for schizophrenia are poorly addressed by existing therapies and represent a large unmet medical need in schizophrenia therapy. Despite this worldwide sales of antipsychotic drugs exceed $12 billion (€9.3 billion).

Related topics Preclinical Research

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