Novel Gonadotropin-Releasing Hormone Antagonists: Peptides Incorporating Modified Nω-Cyanoguanidino Moieties

Article abstract of DOI:10.1021/jm00112a013

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 N^ω-cyano-N^ω'-alkyl- or -arylhomoarginine, -arginine, or -p-aminophenylalanine and N^ω-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 N^ω-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 N^ω-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, 1,DCpa²,DPal³,Lys⁵(atz),DLys⁶(atz),ILys⁸,DAla¹⁰>GnRH), inhibited ovulation in the rat by 90percent at 2 μg/rat with an ED50 in the in vitro histamine release assay comparable to that of GnRH itself.