Novel, Potent Luteinizing Hormone-Releasing Hormone Antagonists with Improved Solubility in Water

Article abstract of DOI:10.1021/jm00040a017

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 ε-amino group with different heterocyclic carboxylic acids or amino-substituted heterocyclic carboxylic acids was synthesized.These novel analogs were synthesized on a solid-phase support via the acylation of lysine residue in otherwise protected resin-bound peptides.All analogs were tested in the rat antiovulatory assay (AOA) and the best of them in in vitro histamine release assay.Introduction of lusine 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 in terms of activity, histamine release, and solubility was nictide: NAcDNal-DCpa-DPal-Ser-PicLys-D(6ANic)-Orn-Leu-ILys-Pro-DAlaNH2 (6ANic = 6-aminonicotinoyl).