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

Eur J Med Chem. 2009 Dec;44(12):4904-19. doi: 10.1016/j.ejmech.2009.08.002. Epub 2009 Aug 6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids* / chemical synthesis
  • Amino Acids* / chemistry
  • Amino Acids* / pharmacology
  • Animals
  • Blood Platelets / drug effects*
  • Cells, Cultured
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacology*
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Quantitative Structure-Activity Relationship
  • Rats
  • Swine
  • Tetrahydroisoquinolines* / chemical synthesis
  • Tetrahydroisoquinolines* / chemistry
  • Tetrahydroisoquinolines* / pharmacology

Substances

  • Amino Acids
  • Fibrinolytic Agents
  • Tetrahydroisoquinolines
  • 1,2,3,4-tetrahydroisoquinoline