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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Benzylpiperidine variations on histamine H3 receptor ligands for improved drug-likeness
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Benzylpiperidine variations on histamine H3 receptor ligands for improved drug-likeness

机译：组胺H3受体配体改善药物相似性的苄基哌啶变化

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摘要

Several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. Nevertheless, many promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity and their dibasic character. Analysis of previously, as potential PET ligands synthesized compounds (ST-889, ST-928) revealed promising results concerning physicochemical properties and drug-likeness. Herein, the synthesis, the evaluation of the binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties of further novel benzylpiperidine variations on H3R antagonists is described. Due to the introduction of various small hydrophilic moieties in the structure, drug-likeness parameters have been improved. For instance, compound 12 (ST-1032) showed in addition to high affinity at the H3R (pKi (hH3R) = 9.3) c log S, c log P, LE, LipE, and LELP values of -2.48, 2.18, 0.44, 7.14, and 4.95, respectively. Also, the keto derivative 5 (ST-1703, pKi (hH 3R) = 8.6) revealed LipE and LELP values of 5.25 and 6.84, respectively.
机译：几个HH3R拮抗剂/反向激动剂进入临床阶段，以广泛的主要是中央发生的疾病。尽管如此，许多有前途的候选人因其药代动力学概况而失败，主要是因为它们具有强烈的亲脂性和它们的二元性质。以前分析，作为潜在的PET配体合成化合物（ST-889，ST-928）揭示了关于物理化学性质和药物相似性的有希望的结果。这里，描述了合成，HH3R在HH 3R的结合特性的评价及对H3R拮抗剂的进一步新苄基哌啶变化的不同物理化学和药物似的特性的估计。由于在结构中引入了各种小型亲水部分，药物相似度参数得到了改善。例如，化合物12（ST-1032）除了在H3R的高亲和力之外（PKI（HH3R）= 9.3）C log S，C log p，Le，Lipe和LELP值的-2.48,2.44，分别为7.14和4.95。此外，酮衍生物5（ST-1703，PKI（HH 3R）= 8.6）分别显示出5.25和6.84的LIPE和LELP值。

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  • 作者

    WingenK.; SchwedJ.S.; IsenseeK.; WeizelL.; ?ivkovi?A.; OdazicD.; StarkH.;

  • 作者单位

    Johann Wolfgang Goethe University Institute of Pharmaceutical Chemistry Biozentrum Max-von-Laue;

    Heinrich Heine University Duesseldorf Institute of Pharmaceutical and Medicinal Chemistry;

    Johann Wolfgang Goethe University Institute of Pharmaceutical Chemistry Biozentrum Max-von-Laue;

    Johann Wolfgang Goethe University Institute of Pharmaceutical Chemistry Biozentrum Max-von-Laue;

    Heinrich Heine University Duesseldorf Institute of Pharmaceutical and Medicinal Chemistry;

    Johann Wolfgang Goethe University Institute of Pharmaceutical Chemistry Biozentrum Max-von-Laue;

    Heinrich Heine University Duesseldorf Institute of Pharmaceutical and Medicinal Chemistry;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    Antagonists; Drug-likeness; GPCR; Lipophilicity;

    机译：拮抗剂;药物相似;gpcr;亲脂性;

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