352303-75-4Relevant academic research and scientific papers
Synthesis and structure-activity relationships of 1-arylmethyl-3-(2-aminopropyl)-5-aryl-6-methyluracils as potent GnRH receptor antagonists
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
, p. 3311 - 3315 (2003)
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
5-Aryluracils as potent GnRH antagonists-Characterization of atropisomers
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
scheme or table, p. 3344 - 3349 (2009/04/11)
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.
3-[(2R)-amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3- methoxyphenyl)-6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization
Tucci, Fabio C.,Zhu, Yun-Fei,Struthers, R. Scott,Guo, Zhiqiang,Gross, Timothy D.,Rowbottom, Martin W.,Acevedo, Oscar,Gao, Yinghong,Saunders, John,Xie, Qiu,Reinhart, Greg J.,Liu, Xin-Jun,Ling, Nicholas,Bonneville, Anne K. L.,Chen, Takung,Bozigrian, Haig,Chen, Chen
, p. 1169 - 1178 (2007/10/03)
Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6- difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-di-one (R-13b, NBI 42902) displayed subnanomolar binding affinity (Ki = 0.56 nM) and was a potent functional antagonist (IC50 = 3.0 nM in Ca 2+ flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (Ki = 3.9 nM). In addition, R-13b had good plasma exposure in cynomolgus monkeys after oral administration, with a Cmax of 737 ng/mL and an AUC of 2392 ng/mL·h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.
Synthesis and Structure-Activity Relationships of 1-Arylmethyl-5-aryl-6-methyluracils as Potent Gonadotropin-Releasing Hormone Receptor Antagonists
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
, p. 1259 - 1271 (2007/10/03)
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
