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Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidine-2,4-dione derivatives as potent GnRH receptor antagonists. 2003

Zhiqiang Guo, and Yongsheng Chen, and Dongpei Wu, and Yun-Fei Zhu, and R Scott Struthers, and John Saunders, and Qiu Xie, and Chen Chen
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA. zguo@neurocrine.com

The synthesis and SAR studies of thieno[2,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists to treat reproductive diseases are discussed. It was found that the 2-(2-pyridyl)ethyl group on the 5-aminomethyl functionality of the core structure was a key feature for good receptor binding activity. SAR study of the 6-(4-aminophenyl) group suggests that hydrophobic substituents were preferred. The best compound from this series had binding affinity (K(i)) of 0.4 nM to the human GnRH receptor.

UI MeSH Term Description Entries
D011744 Pyrimidinones Heterocyclic compounds known as 2-pyrimidones (or 2-hydroxypyrimidines) and 4-pyrimidones (or 4-hydroxypyrimidines) with the general formula C4H4N2O. Pyrimidinone,Pyrimidone,Pyrimidones
D011966 Receptors, LHRH Receptors with a 6-kDa protein on the surfaces of cells that secrete LUTEINIZING HORMONE or FOLLICLE STIMULATING HORMONE, usually in the adenohypophysis. LUTEINIZING HORMONE-RELEASING HORMONE binds to these receptors, is endocytosed with the receptor and, in the cell, triggers the release of LUTEINIZING HORMONE or FOLLICLE STIMULATING HORMONE by the cell. These receptors are also found in rat gonads. INHIBINS prevent the binding of GnRH to its receptors. GnRH Receptors,Gonadoliberin Receptors,Gonadorelin Receptors,Gonadotropin Releasing-Hormone Receptors,LHFSHRH Receptors,LHRH Receptors,Luliberin Receptors,Receptors, GnRH,Receptors, Gonadoliberin,Receptors, Gonadorelin,Receptors, Luliberin,Follicle Stimulating Hormone-Releasing Hormone Receptors,GnRH Receptor,Gonadorelin Receptor,Gonadotropin-Releasing Hormone Receptor,LHRH Receptor,Luteinizing Hormone Releasing Hormone Receptors,Luteinizing Hormone Releasing-Hormone Receptor,Receptor, LHRH,Receptors, Gonadotropin Releasing-Hormone,Receptors, LHFSHRH,Follicle Stimulating Hormone Releasing Hormone Receptors,Gonadotropin Releasing Hormone Receptor,Gonadotropin Releasing Hormone Receptors,Hormone Receptor, Gonadotropin-Releasing,Luteinizing Hormone Releasing Hormone Receptor,Receptor, GnRH,Receptor, Gonadorelin,Receptor, Gonadotropin-Releasing Hormone,Receptors, Gonadotropin Releasing Hormone,Releasing-Hormone Receptors, Gonadotropin
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013876 Thiophenes A monocyclic heteroarene furan in which the oxygen atom is replaced by a sulfur. Thiophene

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