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 nove...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-07, Vol.37 (14), p.2238-2241
Main Authors: Janecka, Anna, Janecki, Tomasz, Shan, Si-mei, Bowers, Cyril, Folkers, Karl
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Gonadotropin-Releasing Hormone - antagonists & inhibitors
Gonadotropin-Releasing Hormone - chemistry
Molecular Sequence Data
Rats
Solubility
Structure-Activity Relationship
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Summary: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).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00040a017