134457-28-6Relevant articles and documents
Structure-activity relationship studies of gonadotropin-releasing hormone antagonists containing S-aryl/alkyl norcysteines and their oxidized derivatives
Samant, Manoj P.,White, Richard,Hong, Doley J.,Croston, Glenn,Conn, P. Michael,Janovick, Jo Ann,Rivier, Jean
, p. 2067 - 2077 (2008/02/03)
A series of acyline analogues incorporating L- and D-isomers of S-arylated/alkylated norcysteines [Ncy(R), where R is 2-naphthyl, methyl, and isopropyl] at positions 1, 4, 7, and 10 were synthesized. Some of these analogues were mono- and dioxidized to sulfoxides and sulfones. All of the analogues of acyline were screened for the antagonism of the GnRH-induced response in a reporter gene assay in HEK-293 cells expressing the human GnRH receptor. Nine of the analogues (9, 11, 15, 16, 17, 19, 20, 21, and 22) had antagonistic potency (IC50 50 = 0.52 nM) in this assay. Selected analogues (9, 11, 15, 16, 19, and 21) were tested in vitro for their antagonism at the rat GnRH-R in a reporter gene assay as well as in an in vivo intact male rat assay. Analogues 9 and 15 were the most potent in suppressing testosterone levels.
Novel Gonadotropin-Releasing Hormone Antagonists: Peptides Incorporating Modified Nω-Cyanoguanidino Moieties
Theobald, Paula,Porter, John,Rivier, Catherine,Corrigan, Anne,Hook, William,et al.
, p. 2395 - 2402 (2007/10/02)
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, 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.
