Identification of 1-Arylmethyl-3- (2-aminoethyl)-5-aryluracil as Novel Gonadotropin-Releasing Hormone Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 46; no. 11; pp. 2023 - 2026
• Main Authors: Zhu, Yun-Fei, Gross, Timothy D, Guo, Zhiqiang, Connors, Patrick J, Gao, Yinghong, Tucci, Fabio C, Struthers, R. Scott, Reinhart, Greg J, Saunders, John, Chen, Ta Kung, Killam Bonneville, Anne L, Chen
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 22-05-2003
• Subjects: Animals; Biological and medical sciences; Drug Stability; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; In Vitro Techniques; Medical sciences; Metabolic Clearance Rate; Mice; Microsomes, Liver - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Receptors, LHRH - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship; Uracil - chemical synthesis; Uracil - chemistry; Uracil - pharmacology; Nitrogen heterocycle; Peptide hormone; Gonadotropin RH; Non peptide compound; In vitro; Structure activity relation; Six membered ring; Tertiary amine; Peptidergic receptor; Benzenic compound; Pyrimidine derivatives; Fluorine Organic compounds; Antagonist; Hormone releasing factor; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm034041s

Based on SAR from bicyclic GnRH antagonists such as 6-aminomethyl-7-arylpyrrolo[1,2-a]pyrimid-4-ones (1) and 2-aryl-3-aminomethylimidazolo[1,2-a]pyrimid-5-ones (2a,b), a series of novel uracil compounds (4) were derived as the GnRH antagonists. Their syntheses and initial SAR are discussed herein. This is the first time that monocycle-based GnRH receptor antagonists are reported.