(3S)-N-(L-Aminoacyl)-1,2,3,4-tetrahydroisoquinoIines, a class of novel antithrombotic agents: Synthesis, bioassay, 3D QSAR, and ADME analysis
To increase antithrombotic activity. 3S-tetrahydroisoquinoline-3-carboxylic acid (1) was modified with natural amino acids to form 19 novel dipeptide analogs, 3S-tetrahydroisoquinoline-3-carboxyamino acids (5a-s), targeting the intestinal peptide transport system. In vitro assay of 5a-s indicated that their potencies for inhibiting adenosine diphosphate (ADP), arachidonic acid (AA), platelet-activating factor (PAF), and thrombin (TH)-induced platelet aggregations were higher than that of 1. Additionally, in vivo assay of 5a-s indicated that their potencies for inhibiting thrombogenesis in rats were also higher than that of 1. Among the candidates. 5h with Ser attachment showed the most impressive features for further development. According to molecular field analysis based Cerius2 QSAR module, two equations (r, 0.961 and 0.988) correlating the structures with both in vitro and in vivo activities of 5a-s were estab lished. ADMET calculations predict higher intestinal absorption for compounds 5a-s. Further investiga tion with Sh as a lead compound is underway.
Tetrahydroisoquinoline Amino acid Antithrombotic 3D QSAR ADMET
Meiqing Zheng Xiaoyi Zhang Ming Zhao Heng Wei Chang Wei Wang Yuji Wang Shiqi Peng
College of Pharmaceutical Sciences.Capital Medical University, Beijing 100069, PR China C S Bio Company.20 Kelly Court, Menlo Park, CA 94025, USA College of Pharmaceutical Sciences.Capital Medical University, Beijing 100069, PR Chit
国际会议
广州
英文
284-297
2008-11-01（万方平台首次上网日期，不代表论文的发表时间）