Scientists from biocrea and Pfizer reported details on the design and synthesis of novel, brain-penetrating phosphodiesterase-10 (PDE10) inhibitors. In a collaborative effort, the researchers have eliminated undesired activity on adenosine receptors and improve the compounds´ physicochemical properties and potency.
The team started with initial high-throughput hits characterized by low potency and selectivity. Further lead optimization led to a number of compounds with very robust activity in a range of preclinical models of anti-psychotic efficacy. The PDE10 inhibitors produced low levels of catalepsy, suggesting a minimal risk for the induction of side-effects involving the extrapyramidal system (EPS), the most common adverse reaction observed with anti-psychotic drugs.
Phosphodiesterases (PDEs) have been identified as key regulators of intracellular cyclic nucleotide levels in the brain. PDE10 inhibition has two major benefits, mimicking the effects of antagonists of the dopamine-2 receptor, the current standard treatment for psychosis, and the effects of agonists of dopamine-1 receptors, which may decrease the side-effect liabilities while contributing to a pro-cognitive profile.
“The data presented at the 241st ACS National Meeting & Exposition underline the potential of our PDE10 inhibitor programs and the strong PDE expertise of our research team,” said Tom Kronbach, chief executive officer of biocrea. “We are very pleased with the recent progress with our proprietary PDE10 inhibitors and are preparing a selected number of compounds for preclinical development.”
Release Date: May 10, 2011
Filed Under: Drug Discovery