Journal of Medicinal Chemistry p. 2395 - 2402 (1991)
Update date:2022-07-30
Topics:
Theobald, Paula
Porter, John
Rivier, Catherine
Corrigan, Anne
Hook, William
et al.
In order to minimize the deleterious effects of histamine release resulting from the administration to rats and humans of some potent gonadotropin-releasing hormone (GnRH) antagonists, various arginine residues were replaced with the less basic Nω-cyano-Nω'-alkyl- or -arylhomoarginine, -arginine, or -p-aminophenylalanine and Nω-triazolyllysine, -ornithine or -p-aminophenylalanine residues in active analogues.These novel analogues were synthesized on a solid-phase support via a two-step modification of the Nω-NH2 of lysine, ornithine, or p-aminophenylalanineresidues in otherwise protected resin bound peptides.Most analogues were tested in the rat antiovulatory assay (AOA) and three in vitro assays: a pituitary cell culture assay, a binding assay to pituitary cell membranes, and a histamine release assay.Introduction of the cyanoguanidino and Nω-triazolyl moieties into GnRH analogues yielded several water-soluble antagonists which showed a desirable therapeutic ratio (low histamine release activity to high in vivo potency).Among them, "Azaline" (10,
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(1991)