Wingen Kerstin, Schwed J Stephan, Isensee Kathleen, Weizel Lilia, Zivković Aleksandra, Odadzic Dalibor, Stark Holger
Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biozentrum, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany.
Heinrich Heine University Duesseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
Bioorg Med Chem Lett. 2014 May 15;24(10):2236-9. doi: 10.1016/j.bmcl.2014.03.098. Epub 2014 Apr 8.
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) clogS, clogP, 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 (hH3R)=8.6) revealed LipE and LELP values of 5.25 and 6.84, respectively.
几种人组胺H3受体拮抗剂/反向激动剂进入了临床阶段，用于治疗多种主要发生在中枢的疾病。然而，许多有前景的候选药物由于其药代动力学特征而失败，主要原因是它们具有很强的亲脂性和二元碱性。对先前作为潜在PET配体合成的化合物（ST-889、ST-928）的分析显示，在物理化学性质和类药性质方面取得了有前景的结果。本文描述了H3R拮抗剂的新型苄基哌啶变体的合成、对hH3R结合特性的评估以及不同物理化学和类药性质的估算。由于在结构中引入了各种小的亲水性基团，类药参数得到了改善。例如，化合物12（ST-1032）除了对H3R具有高亲和力（pKi（hH3R）=9.3）外，clogS、clogP、LE、LipE和LELP值分别为-2.48、2.18、0.44、7.14和4.95。此外，酮衍生物5（ST-1703，pKi（hH3R）=8.6）的LipE和LELP值分别为5.25和6.84。
