Biotie Therapies GmbH, Meissner Strasse 191, 01445 Radebeul, Germany.
J Med Chem. 2010 Jun 10;53(11):4399-411. doi: 10.1021/jm1002793.
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.
新型咪唑并[1,5-a]吡啶并[3,2-e]吡嗪已被合成并鉴定为强效且选择性的磷酸二酯酶 10A（PDE10A）抑制剂。为了进行体外表征，使用 PDE10A 介导的 cAMP 水解的抑制来建立 QSAR 模型以分析取代效应。该分析的结果通过 PDE10A 与化合物 49 复合物的晶体结构得到补充。在抑制剂和结合位点之间发现了定性上的新相互作用，与先前发表的罂粟碱样抑制剂的晶体结构形成对比。根据 PDE10A 抑制剂的已知抗精神病潜力，MK-801 诱导的大鼠刻板行为和多动可被选定的化合物逆转。因此，已经确定了一类有希望的化合物用于治疗精神分裂症，可避免与当前疗法相关的副作用。
