biocrea and Pfizer jointly presented details on novel PDE10 inhibitors

biocrea, a biopharmaceutical company focusing on novel treatments for disorders of the central nervous system (CNS), today reported details on the design and synthesis of novel, brain-penetrating phosphodiesterase-10 (PDE10) inhibitors developed in collaboration with Pfizer Inc. (NYSE: PFE). The data were featured in joint presentations¹ with Pfizer at the recent 241^st ACS National Meeting & Exposition, an event organized by the American Chemical Society (ACS).

The data demonstrated that the scientists at Pfizer and biocrea were able to eliminate undesired activity on adenosine receptors and to considerably improve the compounds´ physicochemical properties and potency. The team had 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. Moreover, these 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. Mechanistically, PDE10 inhibition has two major benefits, mimicking, (1) the effects of antagonists of the dopamine-2 receptor, the current standard treatment for psychosis, and (2) 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 241^st ACS National Meeting & Exposition underline the potential of our PDE10 inhibitor programs and the strong PDE expertise of our research team,” said Tom Kronbach, CEO 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.”

Formerly a division of Biotie Therapies, biocrea has emerged as one of the leading groups with unique expertise in the creation of novel, brain-penetrating PDE inhibitors. Following the expiry of its collaboration with Pfizer in 2010, biocrea has continued to design new scaffolds for brain-penetrating, best-in-class PDE10 inhibitors and has optimized new leads showing encouraging preclinical data in efficacy models. biocrea’s PDE10 inhibitors show exceptional potential for the treatment of all three symptom complexes of schizophrenia (namely hallucinations, negative symptoms and cognition deficits), and a growing body of evidence supports their utility as a new therapeutic option for Huntington’s disease.

biocrea focuses on the discovery and development of novel drugs for the treatment of debilitating CNS diseases such as schizophrenia, depression, and anxiety. biocrea’s key expertise lies in the discovery and optimization of selective ion channel and enzyme modulators, such as phosphodiesterases (PDEs).

The company has been established by seasoned experts with an exceptional track record in the biopharmaceutical industry (e.g. Asta Medica, Degussa, GlaxoSmithKline, Biotie Therapies). Among others, the team was involved in the discovery and development of the potassium channel opener retigabine and the development of a PDE10 inhibitor portfolio for the treatment of schizophrenia in collaboration with GlaxoSmithKline and Wyeth Pharmaceuticals, now Pfizer.

Following its incorporation in November 2010, biocrea is currently implementing a comprehensive partnering and licensing strategy.

About Phosphodiesterases

Phosphodiesterases (PDEs) are key regulators of signal transduction. As such, they are fundamental in the performance and maintenance of our daily life and health. Moreover, they play a crucial role in the onset and progress of various diseases. Phosphodiesterase inhibition can thus be exploited to treat a wide variety of diseases, e.g. chronic obstructive pulmonary disease (through inhibition of PDE4) or erectile dysfunction (through inhibition of PDE5). Recent studies have revealed a striking distribution pattern of PDEs in the brain, which implies a high therapeutic potential of certain PDEs (e.g. PDE2, PDE10) to treat diseases like Schizophrenia, cognition impairment, Parkinson’s and Huntington´s disease. Brain penetrating PDE inhibitors therefore offer a novel approach for the treatment of these debilitating diseases.

So far, validating the benefit of brain PDE inhibitors in CNS diseases has been difficult because access to brain PDEs is limited by the so-called "blood brain barrier" (BBB). The team of biocrea has overcome these limitations and developed brain-penetrating, highly specific PDE inhibitors that constitute a new generation of promising drug candidates for the treatment of CNS disorders.

¹ Malamas M et al., 241st ACS National Meeting & Exposition Abstract 65 - Imidazo[1,5-a]quinoxalines as selective PDE10A inhibitors for the treatment of schizophrenia, http://redir.ec/Qr3C; Malamas, M. et al., 241st ACS National Meeting & Exposition Abstract 66 - Benzo[e]imidazo[5,1-c][1,2,4]triazines as selective PDE10A inhibitors for the treatment of schizophrenia, http://redir.ec/pl1Q

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