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

Citations Over TimeTop 10% of 2010 papers

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.

Related Papers

• → Increased social interaction in mice deficient of the striatal medium spiny neuron‐specific phosphodiesterase 10A2(2007)93 cited
• → Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A(2009)51 cited
• → Effects of 2-nicotinamidethyl nitrate (SG-75), a new antianginal drug, on the cyclic AMP phosphodiesterase activity.(1980)19 cited
• → cGMP-Binding Phosphodiesterase: Novel Effects of cGMP Binding on the Interaction Between Functional Domains in the Enzyme(1990)
• → A Selective Phosphodiesterase 10A Inhibitor Reduces L-Dopa-Induced Dyskinesia in Parkinsonian Monkeys(2018)