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 epsilon-amino group with different heterocyclic carboxylic acids or amino-substituted heterocyclic carboxylic acids was synthesized. These novel analogs wee 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 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 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).
Janecka
A
A
Institute for Biomedical Research, University of Texas at Austin 78712.
Janecki
T
T
Shan
S M
SM
Bowers
C
C
Folkers
K
K
D000595:Amino Acid Sequence; D000818:Animals; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008969:Molecular Sequence Data; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
D007987:Gonadotropin-Releasing Hormone