N-acylated alpha-amino acids as novel oral delivery agents for proteins.
A series of N-acylated alpha-amino acids were synthesized and shown to improve the oral delivery of two protein drugs, salmon calcitonin (sCT) and interferon-alpha. Forty-five compounds in this series were tested in vivo in rats and primates. A significant positive correlation was found between the log P of the acylated amino acids and the decrease in serum calcium following oral dosage of sCT in rats. Such a correlation was not found for interferon-alpha. These derivatized amino acids only weakly inhibited the activity of trypsin or leucine aminopeptidase. Histological examinations of rat intestinal tissue after oral dosing of acylated amino acid/protein combinations revealed no detectable pathology.
D000215:Acylation; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D002116:Calcitonin / Q000008:administration & dosage*; D002118:Calcium / Q000097:blood; D004337:Drug Carriers; D004791:Enzyme Inhibitors; D005998:Glycine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D016898:Interferon-alpha / Q000008:administration & dosage*; D007422:Intestines / Q000033:anatomy & histology / Q000187:drug effects; D007700:Kinetics; D007930:Leucine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014357:Trypsin / Q000378:metabolism; D014361:Trypsin Inhibitors
D000596:Amino Acids; D004337:Drug Carriers; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D014361:Trypsin Inhibitors; C096263:N-cyclohexanoylleucine; C096264:N-cyclohexanoyl-2-phenylglycine; C028815:salmon calcitonin; D002116:Calcitonin; D007931:Leucyl Aminopeptidase; D014357:Trypsin; D007930:Leucine; D002118:Calcium; D005998:Glycine