Opioid peptide prodrugs

R. T., Acyloxyalkoxy-based cyclic prodrugs of opioid peptides evaluation of their chemical and enzymatic stability as well as their transport properties across Caco-2 cell mono-layers, Pharm. Res., 1999, 36, 24-29. 

Gudmundsson, O. S., Jois, S. D., Vander Velde, D. G., Siahaan, T. J., Wang, B., Borchardt, R. T., The effect of conformation on the membrane permeation of coumarinic acid- and phenylpropionic acid-based cyclic prodrugs of opioid peptides. J. Peptide Res. 1999, 53, 383-392. 

Tang, F., Borchardt, R. T., Characterization of the efflux transport(s) responsible for restricting intestinal mucosa permeation of acyloxy-alkoxy-based cyclic prodrug of the opioid peptide DADLE, Pharm Res. 2002, 19, 780-786. 

Preliminary information useful in prodrug design has been obtained with amino acids attached to model aromatic amines. Thus, N-(naphthalen-2-yl) amides of amino acids (6.1, R=side chain of amino acid, R =H) proved to be of interest as test compounds to monitor peptidase activity such as ami-nopeptidase M (membrane alanyl aminopeptidase, microsomal aminopepti-dase, EC 3.4.11.2) [16][17], In the presence of purified rabbit kidney aminopeptidase M or human cerebrospinal fluid (CSF) aminopeptidase activity, the rate of hydrolysis decreased in the order Ala-> Leu->Arg->Glu-2-naphthyl-amide. Ala-2-naphthylamide, in particular, proved to be a good test compound, as its rate of hydrolysis was influenced by experimental conditions (preparation, inhibitors, etc.), as was the hydrolysis of a number of low-molecular-weight opioid peptides and circulating vasoactive peptides. 

O. S. Gudmundsson, K. Nimkar, S. Gangwar, T. Siahaan, R. T. Borchardt, Phenylpro-pionic Acid-Based Cyclic Prodrugs of Opioid Peptides That Exhibit Metabolic Stability to Peptidases and Excellent Cellular Permeation , Pharm. Res. 1999, 16, 16-23. 

Yang, J.Z.,W. Chen, and R.T. Borchardt. 2002. In vitro stability and in vivo pharmacokinetic studies of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs. 

Liederer BM, Borchardt RT. Stability of oxymethyl-modified coumarinic acid cyclic prodrugs of diastereomeric opioid peptides in biological media from various animal species including human. J Pharm Sci 2005 94 2198-2206. 

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