SYNTHESIS OF LHRH ANTAGONISTS SUITABLE FOR ORAL-ADMINISTRATION VIA THE VITAMIN-B-12 UPTAKE SYSTEM

Conjugates have been synthesized between vitamin B-12 and two lysyl de rivatives of the LHRH antagonist, ANTIDE. Lys(6)-ANTIDE and Lys(8)-ANT IDE were both found to have similar activities to the native analogue in the in vitro pituitary cell assay. The in vitro bioactivity of the VB12-ANTIDE conjugates was preserved following linkage using a number of spacers; however, the in vivo bioactivity was lost. In order to pro duce conjugates which had similar in vivo bioactivity to the native an alogue, it was necessary to link the VB12 to the ANTIDE analogues usin g thiol cleavable spacers. The resultant conjugates had similar activi ty to ANTIDE both in vitro and in vivo and were also found to be much more water soluble than ANTIDE. These VB12-ANTIDE conjugates show pote ntial utility as water soluble ANTIDE analogues for parenteral use and are protease resistant LHRH antagonist analogues suitable for uptake from the intestine via the VB12-transport system following oral admini stration.