A class of novel N-(3 S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)- l-amino acid derivatives: their synthesis, anti-thrombotic activity evaluation, and 3D QSAR analysis

• Published in: European journal of medicinal chemistry Vol. 44; no. 12; pp. 4904 - 4919
• Main Authors: Cheng, Shenling, Zhang, Xiaoyi, Wang, Wei, Zhao, Ming, Zheng, Meiqing, Chang, Heng Wei, Wu, Jianghui, Peng, Shiqi
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.12.2009; Elsevier
• Subjects: 3D QSAR; Amino Acids - chemical synthesis; Amino Acids - chemistry; Amino Acids - pharmacology; Animals; Anti-thrombotic; Biological and medical sciences; Blood Platelets - drug effects; Blood. Blood coagulation. Reticuloendothelial system; Cells, Cultured; Chemistry, Medicinal; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - chemistry; Fibrinolytic Agents - pharmacology; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Modification; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Rats; Science & Technology; Swine; Tetrahydroisoquinoline; Tetrahydroisoquinolines - chemical synthesis; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - pharmacology; Modification; Anti-thrombotic; 3D QSAR; Tetrahydroisoquinoline; METABOLITES; MYOCARDIAL-INFARCTION; PLATELET-AGGREGATION; ANALOGS; RECEPTOR; MECHANISMS; ANTITUMOR-ACTIVITY; ANTIMALARIAL; BIOASSAY; ISOQUINOLINE; Anti-thrombotic in vivo activity; Intravenous administration; Peptides; Rat; Nitrogen heterocycle; Cardiovascular disease; Anticoagulant; Modeling; Vascular disease; Structure activity relation; Molecular model; Antithrombotic agent; Bicyclic compound; Aromatic compound; Chemical synthesis; Rodentia; Prediction; Oral administration; In vitro; Thrombosis; Antiplatelet agent; In vivo; Vertebrata; Chemotherapy; Three dimensional model; Experimental disease; Mammalia; Treatment; Animal; Dipeptides
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2009.08.002

To find new anti-thrombotic agents, a natural amino acid was introduced into the 3-position of anti-platelet aggregation active 3 S-tetrahydroisoquinoline-3-carboxylic acid (THIQA), and 20 novel dipeptide derivatives, 3 S-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. [Display omitted]