Discovery of Imidazo[1,5-a]pyrido[3,2-e]pyrazines as a New Class of Phosphodiesterase 10A Inhibitiors

Abstract

Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.

Phosphodiesterase 2 Inhibitors Promote Axonal Outgrowth in Organotypic Slice Co-Cultures

“…PDE activity was measured by the conversion of [ 3 H]-cAMP and [ 3 H]-cGMP into [ 3 H]-AMP and [ 3 H]-GMP, respectively, as described previously [25]. PDEs 1B, 2A, 3A, 4A, 5A, 7B, 8A, 9A, 10A, and 11A were generated from full-length human recombinant clones.…”

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

“…Results of studies with a new class of inhibitors have also provided support for a role of PDE10 in schizophrenia and related disorders (332) as well as in neuroprotection in a model of Huntingon's disease (124). Biotie Therapies has reported another class of potent and selective PDE10A inhibitors (imidazo [1,5-a]pyrido[3,2-e]pyrazines) (148). Development of effective PDE10 inhibitors is currently one of the most active areas of research in the PDE field and holds promise for treatment of a number of neurological dysfunctions.…”

Effect of PDE10A inhibitors on MK-801-induced immobility in the forced swim test

“…Here, the effect of MP-10 (PF-02545920), a PDE10A inhibitor described by Pfizer that is currently under clinical evaluation, and of WEB-3 and WEB-6, two novel PDE10A inhibitors of biocrea, were evaluated. Both PDE10A inhibitors have been published as example 39 and 49 of a novel structural class by Hoefgen et al (2010). The test doses for each compound were chosen according to their effective doses in the acute murine model of hyperactivity induced by a single treatment of MK-801.…”