Design and synthesis of selective and BBB-permeable gelatinase inhibitors

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Epilepsy is a big problem, according to WHO it affects more than 50M people worldwide, out of which more than 30% do not respond to the current antiepileptic drugs. Furthermore, available drugs only address the symptoms of the disease, namely the seizures, but do not have any effect on the progression of the disease. These facts highlight the need of developing novel and more efficacious therapies for the treatment of this condition.  

Gelatinases (MMP-9 and MMP-2), have been proposed as a novel targets for the treatment of epilepsy. In this regard, elevated levels of expression and activity of these two proteases are observed in brain tissue from patients and animal models with this condition. Gelatinases, in particular MMP-9, are known to be strongly involved in the reorganization of the extracellular matrix, synapse remodeling and axonal damage or sprouting that take place after the seizures. In addition to this, they contribute to the cleavage of blood-brain barrier components. These elements contribute to aberrant neurogenesis and neuron proliferation, neuroinflammation, epileptic circuitry formation and neuronal excitation/inhibition imbalance, which at the end trigger recurrent seizures.

Despite the big interest on having a gelatinase inhibitor for the treatment of epilepsy or other diseases where the levels of these two proteases are increased, its development has been limited by the high structural homology among the twenty-four reported MMP family members, which notably challenges the development of selective inhibitors. The use of none selective MMP inhibitors in clinical trials (oncology) have shown low efficacy and severe side effects. 

Recently, by means of in silico calculations combined with in vitro evaluation, we have been able to develop a novel and selective gelatinase inhibitor. This new compound has also the ability to penetrate through blood-brain barrier in vivo and shows a high proteolytic stability and low cytotoxicity. The development behind this new inhibitor has been published lately at Bioorganic Chemistry and opens the door to new therapies based on the specific inhibition of these two proteases. The outstanding efficacy of this inhibitor in two validated animal models of epilepsy will published in a separated paper in the following months. 

Stay tuned!


Reference article:

A. Bertrán, D. Khomiak, A. Konopka, E. Rejmak, E. Bulska, J. Seco,L. Kaczmarek, T. Tarragó & R. Prades

Design and synthesis of selective and blood-brain barrier-permeable hydroxamate-based gelatinase inhibitors

Bioorganic Chemistry (2019) DOI: 10.1016/j.bioorg.2019.103365