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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
5
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pubmed:dateCreated |
2004-2-19
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pubmed:abstractText |
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 beta-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 alpha-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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BonnevilleAnne L KillamAL,
pubmed-author:ChenTa KungTK,
pubmed-author:ChenYongshengY,
pubmed-author:ConnorsPatrick JPJJr,
pubmed-author:GaoYinghongY,
pubmed-author:GrossTimothy DTD,
pubmed-author:GuoZhiqiangZ,
pubmed-author:MoorjaniManishaM,
pubmed-author:ReinhartGregG,
pubmed-author:RowbottomMartin WMW,
pubmed-author:SaundersJohnJ,
pubmed-author:StruthersR ScottRS,
pubmed-author:TucciFabio CFC,
pubmed-author:XXX,
pubmed-author:YewP RPR,
pubmed-author:ZhuYun-FeiYF
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pubmed:issnType |
Print
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pubmed:day |
26
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pubmed:volume |
47
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1259-71
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pubmed:dateRevised |
2004-11-17
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pubmed:meshHeading |
pubmed-meshheading:14971906-Animals,
pubmed-meshheading:14971906-Area Under Curve,
pubmed-meshheading:14971906-Biological Availability,
pubmed-meshheading:14971906-Calcium,
pubmed-meshheading:14971906-Cell Line,
pubmed-meshheading:14971906-Crystallography, X-Ray,
pubmed-meshheading:14971906-Haplorhini,
pubmed-meshheading:14971906-Humans,
pubmed-meshheading:14971906-Metabolic Clearance Rate,
pubmed-meshheading:14971906-Mice,
pubmed-meshheading:14971906-Microsomes, Liver,
pubmed-meshheading:14971906-Molecular Structure,
pubmed-meshheading:14971906-Radioligand Assay,
pubmed-meshheading:14971906-Receptors, LHRH,
pubmed-meshheading:14971906-Stereoisomerism,
pubmed-meshheading:14971906-Structure-Activity Relationship,
pubmed-meshheading:14971906-Uracil
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pubmed:year |
2004
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pubmed:articleTitle |
Synthesis and structure-activity relationships of 1-arylmethyl-5-aryl-6-methyluracils as potent gonadotropin-releasing hormone receptor antagonists.
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pubmed:affiliation |
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, California 92121, USA. zguo@neurocrine.com
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pubmed:publicationType |
Journal Article
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