دورية أكاديمية
أعرض في EDS

1,4-Disubstituted Piperazin-2-Ones as Selective Late Sodium Current Inhibitors with QT Interval Shortening Properties in Isolated Rabbit Hearts.

التفاصيل البيبلوغرافية
العنوان: 1,4-Disubstituted Piperazin-2-Ones as Selective Late Sodium Current Inhibitors with QT Interval Shortening Properties in Isolated Rabbit Hearts.
المؤلفون: Yang H; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Jing M; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Tian C; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Li B; Department of Cardiology, Peking University First Hospital, Beijing 100034, China., Liao W; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Wang W; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Li Y; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Wang X; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Duan G; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Sun Q; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Huang Z; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.; Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China., Wu L; Department of Cardiology, Peking University First Hospital, Beijing 100034, China.; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
المصدر: Journal of medicinal chemistry [J Med Chem] 2024 Aug 08; Vol. 67 (15), pp. 12676-12694. Date of Electronic Publication: 2024 May 17.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Piperazines*/pharmacology , Piperazines*/chemistry , Piperazines*/chemical synthesis , Piperazines*/pharmacokinetics, Animals ; Rabbits ; HEK293 Cells ; Humans ; Anti-Arrhythmia Agents/pharmacology ; Anti-Arrhythmia Agents/chemistry ; Anti-Arrhythmia Agents/pharmacokinetics ; Anti-Arrhythmia Agents/chemical synthesis ; Sodium Channel Blockers/pharmacology ; Sodium Channel Blockers/chemistry ; Sodium Channel Blockers/chemical synthesis ; Sodium Channel Blockers/pharmacokinetics ; Mice ; Long QT Syndrome/chemically induced ; Structure-Activity Relationship ; Male ; NAV1.5 Voltage-Gated Sodium Channel/metabolism ; Heart/drug effects ; Ether-A-Go-Go Potassium Channels/antagonists & inhibitors ; Ether-A-Go-Go Potassium Channels/metabolism ; ERG1 Potassium Channel/antagonists & inhibitors ; ERG1 Potassium Channel/metabolism ; Cardiac Conduction System Disease
مستخلص: Late sodium current ( I Na ) inhibitors are a new subclass of antiarrhythmic agents. To overcome the drawbacks, e.g., low efficacy and inhibition effect on K + current, of the FDA-approved late I Na inhibitor ranolazine, chain amide 6a - 6q , 1,4-disubstituted piperazin-2-ones 7a - 7s , and their derivatives 8a - 8n were successively designed, synthesized, and evaluated in vitro on the Na V 1.5-transfected HEK293T cells by the whole-cell patch clamp recording assay at the concentration of 40 μM. Among the new skeleton compounds, 7d showed the highest efficacy (IC 50 = 2.7 μM) and good selectivity (peak/late ratio >30 folds), as well as excellent pharmacokinetics properties in mice ( T 1/2 of 3.5 h, F = 90%, 3 mg/kg, po). It exhibited low hERG inhibition and was able to reverse the ATX-II-induced augmentation of late I Na phenotype of LQT3 model in isolated rabbit hearts. These results suggest the application potentials of 7d in the treatments of arrhythmias related to the enhancement of late I Na .
المشرفين على المادة: 0 (Piperazines)
0 (Anti-Arrhythmia Agents)
0 (Sodium Channel Blockers)
0 (NAV1.5 Voltage-Gated Sodium Channel)
0 (Ether-A-Go-Go Potassium Channels)
0 (ERG1 Potassium Channel)
SCR Disease Name: Long QT syndrome type 3
تواريخ الأحداث: Date Created: 20240517 Date Completed: 20240808 Latest Revision: 20240812
رمز التحديث: 20240813
DOI: 10.1021/acs.jmedchem.4c00677
PMID: 38757601
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.4c00677