(3S)-N-(L-Aminoacyl)-1,2,3,4-tetrahydroisoquinolines, 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 Cerius(2) 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 established. ADMET calculations predict higher intestinal absorption for compounds 5a-s. Further investigation with 5h as a lead compound is underway.
College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
Meiqing
M
Zheng
Xiaoyi
X
Zhang
Ming
M
Zhao
Heng Wei
HW
Chang
Wei
W
Wang
Yuji
Y
Wang
Shiqi
S
Peng
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001681:Biological Assay; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D015394:Molecular Structure; D010972:Platelet Activating Factor / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology
D005343:Fibrinolytic Agents; D010972:Platelet Activating Factor; D044005:Tetrahydroisoquinolines; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D013917:Thrombin