A class of novel N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-amino acid derivatives: their synthesis, anti-thrombotic activity evaluation, and 3D QSAR analysis.
To find new anti-thrombotic agents, a natural amino acid was introduced into the 3-position of anti-platelet aggregation active 3S-tetrahydroisoquinoline-3-carboxylic acid (THIQA), and 20 novel dipeptide derivatives, 3S-tetrahydroisoquinoline-3-carboxyamino acids (6a-t), targeting the intestinal peptide transport system were provided. In vitro anti-platelet aggregation assay of 6a-t indicated that their potencies of inhibiting adenosine diphosphate (ADP), arachidonic acid (AA), platelet-activating factor (PAF), and thrombin (TH) induced platelet aggregations were higher than that of THIQA, and the in vivo anti-thrombotic assay of 6a-t indicated that their potencies of inhibiting thrombogenesis in rats were also higher than that of THIQA. According to MFA based Cerius2 QSAR module, using training/test set of 6a,b,d,g-p/6c,e,f,q and training/test set of 6a-p/6q-t, two equations (r, 0.984 and 0.996) correlating the structures with in vitro or in vivo activity of 6a-t were established.
Cheng
Shenling
S
College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
Zhang
Xiaoyi
X
Wang
Wei
W
Zhao
Ming
M
Zheng
Meiqing
M
Chang
Heng Wei
HW
Wu
Jianghui
J
Peng
Shiqi
S
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D002478:Cells, Cultured; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013552:Swine; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D005343:Fibrinolytic Agents; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline