Serine racemase inhibitors

Target and Target Class: Serine racemase, enzyme (pyridoxal-5'-phosphate dependent)

Indications: pain, neurodegenerative disorders

Rationale

The amino acid neurotransmitter L-glutamate and N-methyl-D-aspartate (NMDA) receptors play a key role in several physiological functions, such as excitatory neurotransmission and synaptic plasticity. Apart from their normal role in physiological neurotransmission, excessive activation of NMDA receptor leads to excitotoxic damage which forms the basis of several CNS disease states including neurological disorders such as Alzheimer's and Parkinson's diseases and pathological pain states.

Whereas glycine has long been thought to be the endogenous co-agonist for NMDA receptor activation, a growing body of evidence indicates that, in certain brain areas, the D-amino acid D-serine plays a more relevant role as the endogenous co-agonist at the NMDA glycine_B site.

While the occurrence of D-amino acids in mammals challenges classical concepts in biology (in which only L-amino acids would be present or thought to play physiological roles), recent discoveries have revealed a pivotal role of endogenous D-serine in brain function.

D-serine is particularly abundant in the CNS and is synthesised by the pyridoxal-5'-phosphate (PLP, vitamin B₆)-dependent enzyme serine racemase which converts L-serine into D-serine. In the CNS, serine racemase is mainly localised in glial cells surrounding glutamatergic terminals, although evidence for a neuronal distribution of this enzyme has also been obtained.

Inhibition of serine racemase leads to a decrease of the availability of the co-agonist at glutamatergic synapses and consequently negatively modulates NMDA-mediated neurotransmission. Recent data with serine racemase knock-out mice also strongly support a central role for this enzyme and D-serine in NMDA receptor function.

Serine racemase inhibitors therefore represent an alternative to compounds directly acting at the NMDA receptors as therapeutic means for the treatment of neurodegenerative disorders and pain conditions, holding the potential of having fewer side effects than non selective NMDA-antagonists.

This innovative approach expands Evotec's expertise in the field of NMDA receptor as therapeutic targets.

Status

Evotec's hit -finding strategy has employed both traditional screening of a focussed compound library together with more extensive fragment-based screening. Using this approach, Evotec has identified potent inhibitors of serine racemase.
In addition, Evotec have succeeded in obtaining the crystal structure of the human enzyme at an atomic resolution ideal for structure-based rational drug design.