The discovery of novel small molecule non-peptide gonadotropin releasing hormone (GnRH) receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 12; no. 23; pp. 3467 - 3470
• Main Authors: Luthin, David R., Hong, Yufeng, Pathak, Ved P., Paderes, Genevieve, Nared-Hood, Karen D., Castro, Mary A., Vazir, Haresh, Li, Haitao, Tompkins, Eileen, Christie, Lance, May, John M., Anderson, Mark B.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 02-12-2002; Elsevier
• Subjects: Animals; Biological and medical sciences; Drug Design; Guanidine - analogs & derivatives; Guanidine - pharmacology; Hormone Antagonists - chemistry; Hormone Antagonists - pharmacology; Humans; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Phosphoric Monoester Hydrolases - biosynthesis; Protein Binding; Rats; Receptors, LHRH - antagonists & inhibitors; Receptors, LHRH - metabolism; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - metabolism; Structure-Activity Relationship; Automation; Furan derivatives; Peptide hormone; Combinatorial chemistry; Gonadotropin RH; Non peptide compound; Guanidines; Oxygen heterocycle; In vitro; Naphthalene derivatives; Structure activity relation; Chemical compound library; Peptidergic receptor; Carboxamide; Antagonist; Hormone releasing factor; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(02)00755-2

A novel series of non-peptide derivatives
1,
14, and
15 that bind with high affinity to the human GnRH receptors is discussed. The discovery was made from screening our in-house libraries that contained the active structure
2 along with a trace amount of a second active structure
1 that was derived from an acid-induced rearrangement. From this structure type
1, a series of guanidine and non-guanidine containing analogues were prepared and tested as GnRH receptor antagonists. Compounds derived from this series bind to both human and rat GnRH receptors and antagonize GnRH-mediated increases in inositol phosphate production in cells containing recombinant human receptors. These compounds or their analogues may be useful as therapeutic agents for the treatment of hormone-dependent pathologies including prostate, breast and ovarian cancers.
The discovery of novel guanidine-derived GnRH receptor antagonists
1 (Human GnRH-R
K
i=40
nM) is reported.