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Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-11-20 00:00:00 , DOI: 10.1021/acschemneuro.7b00402 David A. Perrey 1 , Ann M. Decker 1 , Yanan Zhang 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-11-20 00:00:00 , DOI: 10.1021/acschemneuro.7b00402 David A. Perrey 1 , Ann M. Decker 1 , Yanan Zhang 1
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Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX1 potency (Ke = 5.7 nM) and selectivity (>1,760-fold over OX2) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (>200 μM), good CNS permeability (Papp = 14.7 × 10–6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3).
中文翻译：
具有改善的溶解度和CNS渗透性的Orexin-1受体拮抗剂的合成和评价
食欲素是下丘脑神经肽，在包括成瘾行为的动机在内的许多功能中起着重要作用。有人建议将orexin-1受体阻断剂作为治疗药物成瘾的潜在策略。我们以前曾报道过基于四氢异喹啉骨架的OX 1受体拮抗剂，具有出色的OX 1效能和选择性。然而，这些化合物具有高亲脂性（clogP> 5）和低至中等的溶解度。为了改善其性能，我们设计并合成了一系列类似物，其中的7位取代基已知有助于OX 1保留了效价和选择性，并在1-位引入了不同性质的组，如先前研究所示，该位通常可耐受取代。亲脂性较低（clogP = 3.07）的化合物44在钙动员试验中显示出出色的OX 1效能（K e = 5.7 nM）和选择性（比OX 2高1,760倍）。在初步的ADME研究中，有44个药物显示出极好的动力学溶解度（> 200μM），良好的CNS渗透性（在MDCK分析中P app = 14.7×10 –6 cm / sec）和较低的药物流出（流出比= 3.3）。
更新日期：2017-11-21
中文翻译：
具有改善的溶解度和CNS渗透性的Orexin-1受体拮抗剂的合成和评价
食欲素是下丘脑神经肽，在包括成瘾行为的动机在内的许多功能中起着重要作用。有人建议将orexin-1受体阻断剂作为治疗药物成瘾的潜在策略。我们以前曾报道过基于四氢异喹啉骨架的OX 1受体拮抗剂，具有出色的OX 1效能和选择性。然而，这些化合物具有高亲脂性（clogP> 5）和低至中等的溶解度。为了改善其性能，我们设计并合成了一系列类似物，其中的7位取代基已知有助于OX 1保留了效价和选择性，并在1-位引入了不同性质的组，如先前研究所示，该位通常可耐受取代。亲脂性较低（clogP = 3.07）的化合物44在钙动员试验中显示出出色的OX 1效能（K e = 5.7 nM）和选择性（比OX 2高1,760倍）。在初步的ADME研究中，有44个药物显示出极好的动力学溶解度（> 200μM），良好的CNS渗透性（在MDCK分析中P app = 14.7×10 –6 cm / sec）和较低的药物流出（流出比= 3.3）。
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