Synthesis and Evaluation of Novel Coumarin-Based Esterase-Sensitive Cyclic Prodrugs of Peptidomimetic RGD Analogs with Improved Membrane Permeability

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概要

• 論文の詳細を見る

• Earlier, we reported the development of a coumarin-based prodrug system that could be used for the preparation of cyclic prodrugs of opioid peptides. These cyclic prodrugs exhibited excellent membrane permeability characteristics. Therefore, it was of interest to determine the effects of this prodrug strategy on the membrane permeabilities of peptidomimetics which also have low membrane permeabilities. For this study, we have chosen two RGD (Arg-Gly-Asp) peptidomimetics, which have the potentials to be developed clinically as orally active antithrombotic agents. However, the clinical development of oral dosage forms of these RGD analogs has been hindered by their low intestinal mucosal permeability. Therefore, we have synthesized the corresponding coumarin-based cyclic prodrugs of these RGD peptidomimetics, which have the two most polar functional groups, a carboxyl and an amino group, masked as an ester and an amide, respectively. These cyclic prodrugs were shown to have higher membrane interaction potentials, as estimated by their partitioning between aqueous buffer and an immobilized artificial membrane, than the corresponding RGD analogs suggesting that they should exhibit good membrane permeation characteristics. Subsequently, in a separate study these cyclic prodrugs were shown to be 5 to 6-fold more able to permeate monolayers of Caco-2 cells, an in vitro cell culture model of the intestinal mucosa barrier, than the corresponding RGD peptidomimetics.

• 公益社団法人日本薬学会の論文
• 1999-01-15

著者

• WANG Wei

  Department of Mechanical Engineering, Chiba University

• Wang W

  National Laboratory Of Solid State Microstructure And Department Of Physics Nanjing University

• BORCHARDT Ronald

  Department of Medicinal Chemistry and Pharmaceutical Chemistry, School of Pharmacy, The University o

• Borchardt R

  Department Of Pharmaceutical Chemistry The University Of Kansas

• Wang W

  College Of Pharmacy Pusan National University

• WANG Binghe

  Department of Chemistry, North Carolina State University

• CAMENISCH Gian

  Department of Pharmaceutical Chemistry, The University of Kansas

• ELMO Jennifer

  Department of Chemistry, North Carolina State University

• ZHANG Huijuan

  Department of Chemistry, North Carolina State University

• Zhang Huijuan

  Department Of Chemistry North Carolina State University

• Elmo Jennifer

  Department Of Chemistry North Carolina State University

• Camenisch Gian

  Department Of Pharmaceutical Chemistry The University Of Kansas

• Wang B

  North Carolina State Univ. Nc Usa

• Wang Binghe

  Department Of Chemistry North Carolina State University

• Wang Wei

  Department Of General Surgery Shanghai Chang Zheng Hospital Second Military Medical University

• Borchardt Ronald

  Department Of Medicinal Chemistry And Pharmaceutical Chemistry School Of Pharmacy The University Of

• Wang Wei

  Department Of Cardiology Shanghai Xuhui Central Hospital

• Wang Wei

  Department Of Biology Graduate School Chinese Academy Of Sciences Beijing

• Wang Wei

  Department Of Biochemistry Hainan Medical College

• Wang Wei

  National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University

• Wang Wei

  Department of Anesthesiology, China-Japan Friendship Hospital, the Chinese Ministry of Health, Beijing, China

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