Synthesis and Structure−Activity Relationships of 1-Arylmethyl-5-aryl-6-methyluracils as Potent Gonadotropin-Releasing Hormone Receptor Antagonists

Based on the SAR from bicyclic gonadotropin-releasing hormone (GnRH) antagonists such as 6-aminomethyl-7-aryl-pyrrolo[1,2-a]pyrimid-4-ones (5) and 2-aryl-3-aminomethyl-imidazolo[1,2-a]pyrimid-5-ones (6a,b), a series of novel uracil compounds (8) were derived as GnRH antagonists. The synthesis and SA...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2004-02, Vol.47 (5), p.1259-1271
Main Authors: Guo, Zhiqiang, Zhu, Yun-Fei, Gross, Timothy D, Tucci, Fabio C, Gao, Yinghong, Moorjani, Manisha, Connors, Patrick J, Rowbottom, Martin W, Chen, Yongsheng, Struthers, R. Scott, Xie, Qiu, Saunders, John, Reinhart, Greg, Chen, Ta Kung, Bonneville, Anne L. Killam, Chen
Format: Article
Language:English
Subjects:
Animals
Area Under Curve
Biological and medical sciences
Biological Availability
Calcium - antagonists & inhibitors
Calcium - metabolism
Cell Line
Crystallography, X-Ray
Haplorhini
Hormones. Endocrine system
Humans
Medical sciences
Metabolic Clearance Rate
Mice
Microsomes, Liver - metabolism
Molecular Structure
Pharmacology. Drug treatments
Radioligand Assay
Receptors, LHRH - antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
Uracil - analogs & derivatives
Uracil - chemical synthesis
Uracil - pharmacokinetics
Uracil - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Based on the SAR from bicyclic gonadotropin-releasing hormone (GnRH) antagonists such as 6-aminomethyl-7-aryl-pyrrolo[1,2-a]pyrimid-4-ones (5) and 2-aryl-3-aminomethyl-imidazolo[1,2-a]pyrimid-5-ones (6a,b), a series of novel uracil compounds (8) were derived as GnRH antagonists. The synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed herein. Introduction of a small methyl substituent at the β-position of the N3 side-chain improved the GnRH binding potency by 5−10-fold. Introduction of a methyl group of (R)-configuration at the α-carbon of the N-3 side-chain gave a modest improvement in binding affinity over the unsubstituted ethylene analogues. This modification enabled us to make uracil compounds without the labile 2-pyridylethyl motif on the basic nitrogen while still maintained excellent potency against the hGnRH receptor.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm030472z