NOVEL, POTENT LUTEINIZING-HORMONE-RELEASING HORMONE ANTAGONISTS WITH IMPROVED SOLUBILITY IN WATER

A series of luteinizing hormone-releasing hormone antagonists with new substitutions in position 6 or positions 5 and 6 that included lysine acylated at the E-amino group with different heterocyclic carboxylic acids or amino-substituted heterocyclic carboxylic acids was synthesiz ed. These novel analogs were synthesized on a solid-phase support via the acylation of lysine residue in otherwise protected resin-bound pep tides. All analogs were tested in the rat antiovulatory assay (AOA) an d the best of them in in vitro histamine release assay. Introduction o f lysine acylated with amino-substituted heterocyclic carboxylic acids yielded several water-soluble antagonists with good therapeutic ratio (high AOA to low histamine releasing activity). The best antagonist i n terms of activity, histamine release, and solubility was nictide: Pa l-Ser-PicLys-D(6ANic)-Orn-Leu-ILys-Pro-DAlaNH(2) (6ANic = 6-aminonicot inoyl),