caa a22 4500 477127843 CHVBK 20180405111655.0 cr unu---uuuuu 170330e19970801xx s 000 0 eng 10.1023/A:1012149227756 doi (NATIONALLICENCE)springer-10.1023/A:1012149227756 Prodrug and Analog Approaches to Improving the Intestinal Absorption of a Cyclic Peptide, GPIIb/IIIa Receptor Antagonist [Elektronische Daten] [Hiroshi Saitoh, Bruce Aungst] Purpose. The purpose of this study was to test whether structural modifications improve the intestinal absorption of DMP 728 (cyclo(D-Abu-NMeArg-Gly-Asp-Amb)), a GPIIb/IIIa receptor antagonist. Methods. In vitro permeabilities of prodrugs and analogs of DMP 728 across excised rat intestinal segments were determined. Results. n-Butyl and n-octyl esters of DMP 728 were relatively stable during in vitro permeation of rat intestine. Intestinal permeation rates of these compounds were no greater than that of DMP 728, even though the octyl ester was much more lipophilic. A pivaloyloxymethyl ester, which was hydrolyzed to DMP 728 during intestinal permeation, also did not improve permeability. In another approach, analogs with an additional methyl substituent on various amide nitrogens were evaluated. Cyclo(D-Val-NMeArg-Gly-Asp-NMeAmb), cyclo(D-Abu-diN-MeLys-Gly-Asp-Amb), and cyclo(NMeGly-NMeArg-Gly-Asp-Amb) each had about 2-fold greater permeability than DMP 728. Two other analogs with improved permeability were linear Ac-D-Abu-NMeArg-Gly-Asp-Amb and a DMP 728 derivative in which the Asp was rearranged. An analog in which the charged amino acids were replaced by neutral amino acids had permeability similar to DMP 728. Conclusions. Within this series of peptides, hydrogen bonding tendency and structural constraint influenced intestinal permeation, but not always in ways consistent with the literature, whereas charge and lipophilicity were not shown to influence intestinal permeability. The failure of these approaches to improve permeation more significantly could be due to the influence of secretory transport. Plenum Publishing Corporation, 1997 absorption nationallicence peptide nationallicence prodrug nationallicence analog nationallicence intestinal permeability nationallicence GPIIb/IIIa antagonist nationallicence Saitoh Hiroshi DuPont Merck Research Laboratories, P.O. Box 80400, 19880-0400, Wilmington, DE aut Aungst Bruce DuPont Merck Research Laboratories, P.O. Box 80400, 19880-0400, Wilmington, DE aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/8(1997-08-01), 1026-1029 0724-8741 14:8<1026 1997 14 11095 https://doi.org/10.1023/A:1012149227756 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012149227756 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Saitoh Hiroshi DuPont Merck Research Laboratories, P.O. Box 80400, 19880-0400, Wilmington, DE aut NATIONALLICENCE 700 1- Aungst Bruce DuPont Merck Research Laboratories, P.O. Box 80400, 19880-0400, Wilmington, DE aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/8(1997-08-01), 1026-1029 0724-8741 14:8<1026 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer