Epithelial cell permeability of a series of peptidic HIV protease inhibitors: aminoterminal substituent effects.
The influence of the aminoterminal substituent in a homologous series of tetrapeptide analogs on transport across Caco-2 cell monolayers was studied. In a series of pyridylcarboxamide regioisomers, the 2-pyridyl isomer was significantly more permeable than either the 3- or 4-congeners. The uniqueness of this peptide was further suggested by examining the partitioning behavior between heptane and ethylene glycol, a system which has been developed as a simple estimate of the desolvation energy or hydrogen bonding potential of a peptide. In this model, the 2-isomer has a much larger partition coefficient than either the 3- or 4-analogs, consistent with its being less solvated than expected based on simple structural considerations. Factors possibly contributing to this decreased effective polarity could be steric interactions or intramolecular hydrogen bonding.
Conradi
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RA
Drug Delivery Systems Research, Upjohn Laboratories, Upjohn Company, Kalamazoo, MI 49001.
Hilgers
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AR
Burton
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Hester
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JB
D000595:Amino Acid Sequence; D002463:Cell Membrane Permeability / Q000502:physiology*; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D006860:Hydrogen Bonding; D007536:Isomerism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
D017320:HIV Protease Inhibitors; D010455:Peptides