Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile,Journal of Medicinal Chemistry

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Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-20 , DOI: 10.1021/acs.jmedchem.3c02037
Amarachi V Okorom ₁ , Gisela Andrea Camacho-Hernandez ₁ , Kristine Salomon ₂ , Kuo Hao Lee ₁ , Therese C Ku ₁ , Jianjing Cao ₁ , Sung Joon Won ₁ , Jacob Friedman _{1,

3} , Jenny Lam _{1,

3} , James Paule _{1,

3} , Rana Rais ₃ , Benjamin Klein ₁ , Zheng-Xiong Xi ₁ , Lei Shi ₁ , Claus J Loland ₂ , Amy Hauck Newman ₁

Affiliation

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8–091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (K_i range = 3–382 nM). However, only the piperidine analogues (20a–d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.

中文翻译：

对 1-(4-(2-双(4-氟苯基)甲基)亚磺酰基)烷基脂环胺进行修饰，提高代谢稳定性并保留非典型 DAT 抑制剂特性

非典型多巴胺转运蛋白（DAT）抑制剂在精神兴奋剂使用障碍（PSUD）的临床前模型中显示出治疗潜力。在大鼠中，1-(4-(2-((双(4-氟苯基)甲基)亚磺酰基)乙基)-哌嗪-1-基)-丙-2-醇 ( JJC8–091, 3b ) 可有效减少可卡因和甲基苯丙胺的增强作用，但本身并不表现出精神兴奋行为。 DAT 亲和力和代谢稳定性的改善对于发现管道候选药物是必要的。因此，合成了一系列1-(4-(2-双(4-氟苯基)甲基)亚磺酰基)烷基脂环胺并评估了DAT和血清素转运蛋白(SERT)的结合亲和力。用高哌嗪或哌啶环系统替代哌嗪在 DAT 下具有良好的耐受性（ K _i范围 = 3–382 nM）。然而，与之前报道的类似物相比，只有哌啶类似物（ 20a - d ）在大鼠肝微粒体中表现出改善的代谢稳定性。基于小鼠中可忽略不计的运动活性以及预测与 DAT 向内构象结合的分子模型，化合物12b和20a似乎保留了非典型 DAT 抑制剂特征。

更新日期：2023-12-20

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