1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities,Journal of Medicinal Chemistry

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1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-22 , DOI: 10.1021/acs.jmedchem.3c01235
Gyuzel Y Mitronova _{1,

2} , Christine Quentin ₁ , Vladimir N Belov ₁ , Jörg W Wegener _{2,

3} , Kamila A Kiszka ₁ , Stephan E Lehnart _{2,

3}

Affiliation

To discover new multifunctional agents for the treatment of cardiovascular diseases, we designed and synthesized a series of compounds with a cyclopropyl alcohol moiety and evaluated them in biochemical assays. Biological screening identified derivatives with dual activity: preventing Ca²⁺ leak through ryanodine receptor 2 (RyR2) and enhancing cardiac sarco-endoplasmic reticulum (SR) Ca²⁺ load by activation of Ca²⁺-dependent ATPase 2a (SERCA2a). The compounds that stabilize RyR2 at micro- and nanomolar concentrations are either structurally related to RyR-stabilizing drugs or Rycals or have structures similar to them. The novel compounds also demonstrate a good ability to increase ATP hydrolysis mediated by SERCA2a activity in cardiac microsomes, e.g., the half-maximal effective concentration (EC₅₀) was as low as 383 nM for compound 12a, which is 1,4-benzothiazepine with two cyclopropanol groups. Our findings indicate that these derivatives can be considered as new lead compounds to improve cardiac function in heart failure.

中文翻译：

具有环丙醇基团的 1,4-苯并硫氮杂卓及其结构类似物同时具有 RyR2 稳定和 SERCA2a 刺激活性

为了发现治疗心血管疾病的新型多功能药物，我们设计并合成了一系列具有环丙醇部分的化合物，并在生化测定中对其进行了评估。生物筛选鉴定出具有双重活性的衍生物：通过兰尼碱受体 2 (RyR2) 防止 Ca ²⁺渗漏，并通过激活 Ca ²⁺依赖性 ATPase 2a (SERCA2a) 增强心脏肌内质网 (SR) Ca ²⁺负荷。在微摩尔和纳摩尔浓度下稳定 RyR2 的化合物要么在结构上与 RyR 稳定药物或 Rycals 相关，要么具有与它们相似的结构。这些新化合物还表现出良好的能力，可以增加心脏微粒体中 SERCA2a 活性介导的 ATP 水解，例如，化合物 12a 的半最大有效浓度 (EC ₅₀ ) 低至 383 nM，化合物 12a 是 1,4-苯并硫氮杂卓两个环丙醇基团。我们的研究结果表明，这些衍生物可被视为改善心力衰竭心脏功能的新先导化合物。

更新日期：2023-11-22

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