Structure−Activity Relationship Studies of Gonadotropin-Releasing Hormone Antagonists Containing S-Aryl/Alkyl Norcysteines and Their Oxidized Derivatives

• Published in: Journal of medicinal chemistry Vol. 50; no. 9; pp. 2067 - 2077
• Main Authors: Samant, Manoj P, White, Richard, Hong, Doley J, Croston, Glenn, Conn, P. Michael, Janovick, Jo Ann, Rivier, Jean
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 03-05-2007
• Subjects: Animals; Biological and medical sciences; Butyrates - chemical synthesis; Butyrates - pharmacology; Cell Line; Cercopithecus aethiops; Cysteine - analogs & derivatives; Cysteine - chemical synthesis; Cysteine - pharmacology; Genes, Reporter; Gonadotropin-Releasing Hormone - antagonists & inhibitors; Gonadotropin-Releasing Hormone - genetics; Hormones. Endocrine system; Humans; Leucine - analogs & derivatives; Leucine - chemical synthesis; Leucine - pharmacology; Male; Medical sciences; Naphthalenes - chemical synthesis; Naphthalenes - pharmacology; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; Oxidation-Reduction; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Solubility; Stereoisomerism; Sulfones - chemical synthesis; Sulfones - pharmacology; Sulfoxides - chemical synthesis; Sulfoxides - pharmacology; Testosterone - antagonists & inhibitors; Testosterone - blood; Human; Oligopeptides; Peptides; Rat; Rodentia; Gonadotropin RH; In vitro; In vivo; Vertebrata; Mammalia; Structure activity relation; Sulfur peptide; Animal; Affinity; Peptide synthesis; Antagonist; Solid phase; Chemical synthesis; Hormonal receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0613931

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 < 2 nM) similar to that of acyline (IC50 = 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.