It has previously been reported that a 3-(3-(piperazin-1-yl)propyl)indole series of 5-HT1D receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pKa of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4-fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT1D receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pKa of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.

中文翻译：

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3-（3-（哌啶-1-基-丙基）丙基）吲哚和3-（3-（哌嗪-1-基）丙基）吲哚的氟化产生具有改善的药代动力学特征的选择性人5-HT1D受体配体。

以前已经报道过，3-（3-（哌嗪-1-基）丙基）吲哚系列的5-HT1D受体配体比相应的3-（3-（哌啶-1-基）丙基）吲哚具有药代动力学优势。与哌啶相比，哌嗪的pKa降低可能是这些差异的一种可能解释。为了研究该提议，我们开发了将氟掺入这些配体中的通用合成策略，生产出一系列新的4-氟哌啶，3-氟-4-氨基哌啶，以及哌嗪和哌啶衍生物，其丙基连接基中带有一个或两个氟。 。鉴定了对5-HT1D受体保持高亲和力和选择性并在体外显示激动剂功效的配体。发现掺入氟可显着降低化合物的pKa，