Discovery of novel (6S/12aS)-heptachpyridone capable of inhibiting thrombosis in vivo

Mengyu Hou; Manjie Lv; Xiaoyi Zhang; Yaonan Wang; Shurui Zhao; Jianhui Wu; Shiqi Peng; Ming Zhao

doi:10.1016/j.bmcl.2020.127440

Discovery of novel (6S/12aS)-heptachpyridone capable of inhibiting thrombosis in vivo

Bioorg Med Chem Lett. 2020 Oct 1;30(19):127440. doi: 10.1016/j.bmcl.2020.127440. Epub 2020 Jul 27.

Authors

Mengyu Hou¹, Manjie Lv¹, Xiaoyi Zhang¹, Yaonan Wang¹, Shurui Zhao¹, Jianhui Wu¹, Shiqi Peng², Ming Zhao³

Affiliations

¹ Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China; Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
² Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China; Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China. Electronic address: sqpeng@bjmu.edu.cn.
³ Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China; Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China; Beijing Laboratory of Biomedical Materials and Key Laboratory of Biomedical Materials of Natural Macromolecules, Beijing University of Chemical Technology, Beijing 100026, China. Electronic address: mingzhao@bjmu.edu.cn.

PMID: 32730945
DOI: 10.1016/j.bmcl.2020.127440

Abstract

The in vitro conversion of (1S,3S)-1-dimethoxylethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, (1S,3S)-DCCA, in rat plasma is monitored by HPLC-FT-ICR-MS. We show that the in vitro conversion of (1S,3S)-DCCA in rat plasma for 1 h leads to forming (6S/12aS)-bisdimethoxyethylheptachpyridone, reflecting intermolecular condensation of (1S,3S)-DCCA, and the in vitro conversion of (6S/12aS)-bisdimethoxyethylheptachpyridone in rat plasma for 1 h leads to forming (6S/12aS)-heptachpyridone, reflecting hydrolysis of (6S/12aS)-bisdimethoxyethylheptachpyridone. At a dose of 1.0 μmol/kg (6S/12aS)-heptachpyridone orally inhibits venous thrombosis and arterial thrombosis in vivo. Bleeding time, clotting time and international normalized ratio show that at this dose (6S/12aS)-heptachpyridone has no bleeding risk, does not lengthen clotting time and does not change the exogenous coagulation pathway. We also show that the reactions promoted by rat plasma are easy to practice by chemical synthesis. Thus our findings build a bridge across the in vivo conversion and the application.

Keywords: Arterial thrombosis; Bleeding; HPLC-MS; Metabolism; Venous thrombosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood / metabolism
Carbazoles / chemical synthesis
Carbazoles / metabolism
Carbazoles / therapeutic use*
Diketopiperazines / chemical synthesis
Diketopiperazines / metabolism
Diketopiperazines / therapeutic use*
Fibrinolytic Agents / chemical synthesis
Fibrinolytic Agents / metabolism
Fibrinolytic Agents / therapeutic use*
Hydrolysis
Male
Rats, Sprague-Dawley
Vena Cava, Inferior / drug effects
Venous Thrombosis / drug therapy*

Substances

Carbazoles
Diketopiperazines
Fibrinolytic Agents