Thrombotic disease is one of the major causes of death in the U.S.; in addition, more than one and one-half million people are hospitalized with myocardial infarctions each year. There has been tremendous progress in the development of RGD-peptidomimetic-derived antithrombotic agents, which may potentially lead to drugs to combat thrombosis. Unfortunately, RGD-peptidomimetics have poor oral bioavailability because they have physicochemical properties unfavorable to permeation through cell membranes, which is a common problem for peptides and peptidomimetics. The low membrane permeation of RGD-peptidomimetics is due to their physicochemical properties , including size, charge, solubility, hydrogen-bonding potential, enzyme stability and conformation. This proposal investigates the possibility of temporarily changing the physicochemical properties of some known RGD-peptidomimetics to increase their ability to permeate membranes by implementing the cyclic drug methodology, developed in our laboratory. Therefore, the objectives of this proposal are to synthesize cyclic prodrugs (1) from RGD-peptidomimetics (1a) and to study their ability to permeate cell membranes compared to that of the parent compound. The formation of cyclic prodrugs of RGD-peptidomimetics (1) will transiently mask the unfavorable physicochemical properties of the parent drug and will reduce the charges and hydrogen-bonding potential, improve enzymatic stability and induce folding to form a compact structure. Therefore, the change in physical properties can improve their permeation through cell membranes. After crossing the cell membrane, cyclic prodrug 1 can be hydrolyzed by esterase to release the parent compound 1a. The improvement of cell membrane permeation of the cyclic prodrug of RGD-peptidomimetics compared to their respective parent compounds will be evaluated using the Caco-2 cell culture model and the intestinal rat perfusion model. The physicochemical properties of the cyclic prodrugs will be used to explain the cell membrane permeation characteristics of the cyclic prodrugs an the parent compounds. Several physicochemical properties of the prodrugs and the parent compounds will be evaluated, including solubility, hydrogen bonding potential, average hydrodynamic volumes, partition coefficients, lipophilicity and conformation. The enzymatic stability of the cyclic prodrugs of HIV-protease inhibitors will be examined in different biological media including rat intestinal homogenates, rat liver homogenates, Caco-2 cell homogenates, human plasma and isolated enzymes. The biological activity of the cyclic prodrugs of RGD-peptidomimetics and their respective parent compounds will be evaluated.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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University of Kansas Lawrence
Schools of Pharmacy
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He, H T; Xu, C R; Song, X et al. (2003) Syntheses of cyclic prodrugs of RGD peptidomimetics with various macrocyclic ring sizes: evaluation of physicochemical, transport and antithrombic properties. J Pept Res 61:331-42
Song, Xiaoping; Siahaan, Teruna J (2002) Synthesis and stability study of a modified phenylpropionic acid linker-based esterase-sensitive prodrug. Bioorg Med Chem Lett 12:3439-42
Yusuf-Makagiansar, Helena; Anderson, Meagan E; Yakovleva, Tatyana V et al. (2002) Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases. Med Res Rev 22:146-67
Song, Xiaoping; He, Henry T; Siahaan, Teruna J (2002) Synthesis of cyclic prodrugs of Aggrastat and its analogue with a modified phenylpropionic acid linker. Org Lett 4:549-52
Mahadevan, Janaki; Xu, Christine; Siahaan, Teruna et al. (2002) Molecular dynamics simulations of conformational behavior of linear RGD peptidomimetics and cyclic prodrugs in aqueous and octane solutions. J Biomol Struct Dyn 19:775-88
Yusuf-Makagiansar, H; Makagiansar, I T; Siahaan, T J (2001) Inhibition of the adherence of T-lymphocytes to epithelial cells by a cyclic peptide derived from inserted domain of lymphocyte function-associated antigen-1. Inflammation 25:203-14
Makagiansar, I T; Avery, M; Hu, Y et al. (2001) Improving the selectivity of HAV-peptides in modulating E-cadherin-E-cadherin interactions in the intercellular junction of MDCK cell monolayers. Pharm Res 18:446-53
Bogdanowich-Knipp, S J; Jois, D S; Siahaan, T J (1999) The effect of conformation on the solution stability of linear vs. cyclic RGD peptides. J Pept Res 53:523-9
Bogdanowich-Knipp, S J; Chakrabarti, S; Williams, T D et al. (1999) Solution stability of linear vs. cyclic RGD peptides. J Pept Res 53:530-41
Bogdanowich-Knipp, S J; Jois, S D; Siahaan, T J (1999) Effect of conformation on the conversion of cyclo-(1,7)-Gly-Arg-Gly-Asp-Ser-Pro-Asp-Gly-OH to its cyclic imide degradation product. J Pept Res 54:43-53