Parallel Synthesis of 2-Aryl-4-aminobenzimidazoles and Their Evaluation as Gonadotropin Releasing Hormone Antagonists

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• 作者：Daniel M. Green ; Igor Goljer ; Diane S. Andraka ; Murty Chengalvala ; Linda Shanno ; Warren Hurlburt ; Jeffrey C. Pelletier
• 刊名：Journal of Combinatorial Chemistry
• 出版年：2009
• 出版时间：January 12, 2009
• 年：2009
• 卷：11
• 期：1
• 页码：117-125
• 全文大小：209K
• 年卷期：v.11,no.1(January 12, 2009)
• ISSN：1520-4774

文摘

2-Trifluoromethyl-4-aminobenzimidazoles were previously identified by screening to be active antagonists of the gonadotropin releasing hormone receptor (GnRH-R). Structure activity relationships and diversity oriented synthesis are shown here in greater detail. 2-Substituted benzimidazoles were synthesized in parallel by the coupling of carboxylic acids with a latent intermediate diamine monomer to yield the desired benzimidazoles in fair yields. A catch and release strategy was employed as a product isolation technique, followed by RP-HPLC to obtain products of desired purity for biological evaluation. Two libraries were prepared and screened to determine the optimal substitution for inhibitory activity against GnRH-R. The initial library focused on substituted phenyl, pyridine, and thiophenes. The follow-up library focused on substitution patterns observed in the initial library members and generated compounds with IC₅₀ values lower than 100 nM at the GnRH-R.