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Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-30 , DOI: 10.1021/acs.jmedchem.9b01938 Predrag Kalaba 1 , Marija Ilić 1 , Nilima Y Aher 1 , Vladimir Dragačević 1 , Marcus Wieder 1 , Martin Zehl 2 , Judith Wackerlig 1 , Stanislav Beyl 3 , Simone B Sartori 4 , Karl Ebner 4 , Alexander Roller 5 , Natalie Lukic 5 , Tetyana Beryozkina 6 , Eduardo Rene Perez Gonzalez 7 , Philip Neill 1 , Jawad Akbar Khan 8 , Vasiliy Bakulev 6 , Johann Jakob Leban 1 , Steffen Hering 3 , Christian Pifl 9 , Nicolas Singewald 4 , Jana Lubec 10 , Ernst Urban 1 , Harald H Sitte 8 , Thierry Langer 1 , Gert Lubec 10
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-30 , DOI: 10.1021/acs.jmedchem.9b01938 Predrag Kalaba 1 , Marija Ilić 1 , Nilima Y Aher 1 , Vladimir Dragačević 1 , Marcus Wieder 1 , Martin Zehl 2 , Judith Wackerlig 1 , Stanislav Beyl 3 , Simone B Sartori 4 , Karl Ebner 4 , Alexander Roller 5 , Natalie Lukic 5 , Tetyana Beryozkina 6 , Eduardo Rene Perez Gonzalez 7 , Philip Neill 1 , Jawad Akbar Khan 8 , Vasiliy Bakulev 6 , Johann Jakob Leban 1 , Steffen Hering 3 , Christian Pifl 9 , Nicolas Singewald 4 , Jana Lubec 10 , Ernst Urban 1 , Harald H Sitte 8 , Thierry Langer 1 , Gert Lubec 10
Affiliation
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Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the S-configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro, and in vivo studies that have demonstrated both safety and efficacy profile of this compound class.
中文翻译：
新型基于噻唑的莫达非尼类似物在单胺转运蛋白上的结构活性关系。
非典型的多巴胺再摄取抑制剂（例如莫达非尼）用于治疗睡眠障碍，并被研究为可卡因成瘾和认知增强的潜在疗法。我们不断努力寻找对多巴胺转运蛋白（DAT）具有更高抑制活性和选择性的莫达非尼类似物，先前已导致了有希望的含噻唑衍生物CE-103，CE-111，CE-123和CE-125。在这里，我们描述了基于这些支架的一系列化合物的合成和活性，从而产生了几种新型的选择性DAT抑制剂，并提供了对结构-活性关系的宝贵见解。第二个手性中心的引入和随后的手性分离提供了所有四种立体异构体，因此，S构型在DAT上通常都表现出最高的活性和选择性。通过计算机，体外和体内研究进一步表征了该系列的代表性化合物，这些研究证明了该化合物类别的安全性和功效。
更新日期：2019-12-31
中文翻译：
新型基于噻唑的莫达非尼类似物在单胺转运蛋白上的结构活性关系。
非典型的多巴胺再摄取抑制剂（例如莫达非尼）用于治疗睡眠障碍，并被研究为可卡因成瘾和认知增强的潜在疗法。我们不断努力寻找对多巴胺转运蛋白（DAT）具有更高抑制活性和选择性的莫达非尼类似物，先前已导致了有希望的含噻唑衍生物CE-103，CE-111，CE-123和CE-125。在这里，我们描述了基于这些支架的一系列化合物的合成和活性，从而产生了几种新型的选择性DAT抑制剂，并提供了对结构-活性关系的宝贵见解。第二个手性中心的引入和随后的手性分离提供了所有四种立体异构体，因此，S构型在DAT上通常都表现出最高的活性和选择性。通过计算机，体外和体内研究进一步表征了该系列的代表性化合物，这些研究证明了该化合物类别的安全性和功效。
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