Dual Targeting of Adenosine A2A Receptors and Monoamine Oxidase B by 4H-3,1-Benzothiazin-4-ones

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• 作者：Anne St枚脽el ; Miriam Schlenk ; Sonja Hinz ; Petra K眉ppers ; Jag Heer ; Michael G眉tschow ; Christa E. M眉ller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4580-4596
• 全文大小：715K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

Blockade of A_2A adenosine receptors (A_2AARs) and inhibition of monoamine oxidase B (MAO-B) in the brain are considered attractive strategies for the treatment of neurodegenerative diseases such as Parkinson鈥檚 disease (PD). In the present study, benzothiazinones, e.g., 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide (13), were identified as a novel class of potent MAO-B inhibitors (IC₅₀ human MAO-B: 1.63 nM). Benzothiazinones with large substituents in the 2-position, e.g., methoxycinnamoylamino, phenylbutyrylamino, or chlorobenzylpiperazinylbenzamido residues (14, 17, 27, and 28), showed high affinity and selectivity for A_2AARs (K_i human A_2AAR: 39.5鈥?9.5 nM). By optimizing benzothiazinones for both targets, the first potent, dual-acting A_2AAR/MAO-B inhibitors with a nonxanthine structure were developed. The best derivative was N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide (17, K_i human A_2A, 39.5 nM; IC₅₀ human MAO-B, 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A_2AAR-induced cAMP accumulation and showed competitive, reversible MAO-B inhibition. The new compounds may be useful tools for validating the A_2AAR/MAO-B dual target approach in PD.