Discovery of Imidazo[1,5-a]pyrido[3,2-e]pyrazines as a New Class of Phosphodiesterase 10A Inhibitiors
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- 作者：Norbert Hfgen ; Hans Stange ; Rudolf Schindler ; Hans-Joachim Lankau ; Christian Grunwald ; Barbara Langen ; Ute Egerland ; Peter Tremmel ; Menelas N. Pangalos ; Karen L. Marquis ; Thorsten Hage ; Boyd L. Harris
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：June 10, 2010
- 年：2010
- 卷：53
- 期：11
- 页码：4399-4411
- 全文大小：1058K
- 年卷期：v.53,no.11(June 10, 2010)
- ISSN：1520-4804
文摘
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.