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首页> 外文期刊>Medicinal chemistry >Synthesis, in vitro activities of (2-cyclopropoxyphenyl)piperidine derivatives for alpha 1a and alpha 1d adrenergic receptor inhibitors.
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Synthesis, in vitro activities of (2-cyclopropoxyphenyl)piperidine derivatives for alpha 1a and alpha 1d adrenergic receptor inhibitors.

机译：（2-环丙氧基苯基）哌啶衍生物对α1a和α1d肾上腺素能受体抑制剂的合成，体外活性。

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摘要

An alpha 1a- and alpha 1d-adrenergic receptor (AR) selective antagonist may be a more efficacious treatment for BPH/LUTS patients and may have fewer side effects than the existing pharmaceuticals. A facile synthesis for a series of (2-cyclopropoxyphenyl)piperidine derivatives has been developed, in which aryl vinyl ether formation and subsequent cyclopropyl formation provide efficient access to key intermediate N-Boc-4-(2-cyclopropoxyphenyl)piperidine. The synthesized (2-cyclopropoxyphenyl)piperidine derivatives display high affinity and selectivity for alpha1a-AR and alpha1d-AR compared to alpha1b-AR and D2 receptor, Ki values for alpha1a-AR are 0.91 nM to 79.0 nM and alpha1d-AR are 2.0 nM to 57 nM; Ki values for alpha1b-AR are 107 nM to 839.8 nM and D2 receptor are 66.2 nM to 187.1 nM. The selectivity ratios of Ki(alpha1b)/Ki(alpha1a) are 11 to 155 fold, Ki(alpha1b)/Ki(alpha1d) are 6 to 171 fold, Ki(D2)/Ki(alpha1a) are 2 to 158 fold, and Ki(D2)/Ki(alpha1d) are 1.2 to 89 fold. Compound 17a shows improved stability in human liver microsome test (t1/2 = 18 minutes).
机译：对于BPH / LUTS患者，α1a和α1d肾上腺素受体（AR）选择性拮抗剂可能是一种更有效的治疗方法，并且可能比现有药物具有更少的副作用。已经开发了一系列（2-环丙氧基苯基）哌啶衍生物的简便合成方法，其中芳基乙烯基醚的形成和随后的环丙基的形成提供了对关键中间体N-Boc-4-（2-环丙氧基苯基）哌啶的有效利用。合成的（2-环丙氧基苯基）哌啶衍生物与alpha1b-AR和D2受体相比，对alpha1a-AR和alpha1d-AR表现出高亲和力和选择性，alpha1a-AR的Ki值为0.91 nM至79.0 nM，alpha1d-AR为2.0 nM至57 nM; alpha1b-AR的Ki值为107 nM至839.8 nM，D2受体为66.2 nM至187.1 nM。 Ki（alpha1b）/ Ki（alpha1a）的选择性比为11至155倍，Ki（alpha1b）/ Ki（alpha1d）的选择性为6至171倍，Ki（D2）/ Ki（alpha1a）的选择性为2至158倍， Ki（D2）/ Ki（alpha1d）是1.2到89倍。化合物17a在人肝微粒体测试中显示出改善的稳定性（t1 / 2 = 18分钟）。

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