- 5-Aryluracils as potent GnRH antagonists-Characterization of atropisomers
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Optimization of a series of uracils bearing a 2-fluoro- or 2-chloro-3-methoxyphenyl group at the 5-position resulted in compounds such as 3d and 3f with subnanomolar binding affinity at the human GnRH receptor. While the 2-fluoro-3-methoxyphenyl compound 3a was characterized as a mixture of interchangeable atropisomers, the diastereoisomers of 2-chloro-3-methoxyphenyl analogs were separated. It was found that the aR-atropisomer was much more potent than the aS-isomer based on the X-ray crystal structure of 3h-II.
- Zhao, Liren,Guo, Zhiqiang,Chen, Yongsheng,Hu, Tao,Wu, Dongpei,Zhu, Yun-Fei,Rowbottom, Martin,Gross, Timothy D.,Tucci, Fabio C.,Struthers, R. Scott,Xie, Qiu,Chen, Chen
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scheme or table
p. 3344 - 3349
(2009/04/11)
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- Discovery of sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6- [trifluoromethyl]-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl] -1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
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The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl) -4-methyl-2,6-dioxo-3,6-dihy-dro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
- Chen, Chen,Wu, Dongpei,Guo, Zhiqiang,Xie, Qiu,Reinhart, Greg J.,Madan, Ajay,Wen, Jenny,Chen, Takung,Huang, Charles Q.,Chen, Mi,Chen, Yongsheng,Tucci, Fabio C.,Rowbottom, Martin,Pontillo, Joseph,Zhu, Yun-Fei,Wade, Warren,Saunders, John,Bozigian, Haig,Struthers, R. Scott
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scheme or table
p. 7478 - 7485
(2009/12/07)
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- Synthesis and Structure-Activity Relationships of 1-Arylmethyl-5-aryl-6-methyluracils as Potent Gonadotropin-Releasing Hormone Receptor Antagonists
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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 d
- Guo, Zhiqiang,Zhu, Yun-Fei,Gross, Timothy D.,Tucci, Fabio C.,Gao, Yinghong,Moorjani, Manisha,Connors Jr., Patrick J.,Rowbottom, Martin W.,Chen, Yongsheng,Struthers, R. Scott,Xie, Qiu,Saunders, John,Reinhart, Greg,Chen, Ta Kung,Bonneville, Anne L. Killam,Chen, Chen
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p. 1259 - 1271
(2007/10/03)
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- Synthesis and structure-activity relationships of uracil derived human GnRH receptor antagonists: (R)-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6- methyluracils containing a substituted thiophene or thiazole at C-5
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The design and synthesis of a number of 5-thiazolyl and 5-thienyl substituted uracils is described and results from SAR studies are summarized. The best compound showed Ki = 2 nM. The synthesis of a series of (R)-3-[2-(2-amino)phenethyl]-1-(2,6
- Rowbottom, Martin W.,Tucci, Fabio C.,Connors Jr., Patrick J.,Gross, Timothy D.,Zhu, Yun-Fei,Guo, Zhiqiang,Moorjani, Manisha,Acevedo, Oscar,Carter, Lee,Sullivan, Susan K.,Xie, Qiu,Fisher, Andrew,Struthers, R. Scott,Saunders, John,Chen, Chen
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p. 4967 - 4973
(2007/10/03)
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- Synthesis and structure-activity relationships of 1-arylmethyl-3-(2-aminopropyl)-5-aryl-6-methyluracils as potent GnRH receptor antagonists
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The novel synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed. Introduction of a small methyl substituent at the β-position from N3 of the uracil improved the GnRH binding potency by 5- to 10-fold. The best compou
- Guo, Zhiqiang,Zhu, Yun-Fei,Tucci, Fabio C.,Gao, Yinghong,Struthers, R. Scott,Saunders, John,Gross, Timothy D.,Xie, Qiu,Reinhart, Greg J.,Chen, Chen
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p. 3311 - 3315
(2007/10/03)
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- Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
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GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein A, Q, R1, R2, R3a, R3b, R4, R5, R6 and n are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
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