PDE10a Inhibitors

Target: Phosphodiesterase 10a, Enzyme

Indications: Schizophrenia, Metabolic Syndrome

Rationale

Cyclic nucleotide second messengers (cAMP and cGMP) play a central role in signal transduction and the regulation of physiological responses. In mammals, their intracellular levels are controlled by the superfamily of cyclic nucleotide phosphodiesterase (PDE) enzymes. These metallophosphohydrolases (e.g. Mg²⁺ and Zn²⁺) specifically cleave the 3',5'-cyclic phosphate moiety of cAMP and/or cGMP to their inactive 5' monophosphates and thus provide the major pathway for terminating the cyclic nucleotide signal for the cell.

Members of the PDE superfamily differ in biochemical properties, tissue distributions, substrate and inhibitor specificities and regulatory mechanisms.

The PDEs are divided into 11 families based on sequence homology within the catalytic domain, which results in similar substrate specificity and sensitivity to pharmacological inhibitors within a family. Within each family, there are multiple isoforms with at least 44 distinct forms expressed in humans (e.g. PDE1a, PDE1b etc). PDE10a is a dual-substrate enzyme (although its affinity for cAMP is greater than for cGMP). Of the 11 PDE families, PDE10a has the most restricted distribution. PDE10a mRNA is highly expressed only in brain, pancreatic islet cells and testes. In the brain, PDE10a mRNA and protein are highly enriched in one population of neurons, the medium spiny projection neurons (MSNs) of the striatum.

The striatal MSNs function as the principal input site of the basal ganglia, a series of interconnected sub-cortical nuclei that integrate cortical and dopaminergic inputs to facilitate planning and execution of relevant motor and cognitive patterns while suppressing unwanted or irrelevant patterns. Dysfunction in the basal ganglia circuit has been implicated in various CNS disorders, including Parkinson's disease, Huntington's disease, schizophrenia, obsessive-compulsive disorder and addiction.

Preclinical evidence supports a role for PDE10a inhibitors in schizophrenia. PDE10a knock out mice have comparable responses to clinically used antipsychotics in predictive models. Moreover PDE10a knock out mice show increased social interaction and non selective PDE10a inhibitors improve cognitive deficits, suggesting that PDE10a inhibitors have the potential of also improving negative and cognitive symptoms in schizophrenia.

PDE10a is also expressed in pancreatic islet cells; inhibitors have been shown to be insulin secretagogues. It has been found that PDE10a knock out mice fed a high-fat diet are resistant to developing obesity and hyperinsulinemia, compared to wild-type controls. As well as supporting the potential use of PDE10a inhibitors in the treatment of Metabolic Syndrome, these results suggest that PDE10a inhibition may not have the weight-gain liability associated with current antipsychotics.

PDE10a inhibitors therefore represent an attractive and novel therapeutic angle for the treatment of Schizophrenia and Metabolic Syndrome.

At least one selective PDE10a inhibitor is currently in clinical trials. Further support for the inherent 'druggability' of this target class is clear from the various PDE5 inhibitors successfully marketed for erectile dysfunction such as Sildenafil (Viagra).

EVOlution™, Evotec's fragment-based drug discovery (FBDD) platform offers an innovative approach to hit finding. By combining this fragment screening technology with subsequent crystallographic and NMR spectroscopic techniques Evotec has been able to rapidly identify novel and highly-efficient small molecule fragment hits as PDE10a inhibitors.

Status

Evotec has obtained multiple co-crystal structures of its novel PDE10a fragment inhibitors and has started hit-to-lead activities in order to optimize their properties.