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. Jan-Feb 2009;11(1):117-25.
doi: 10.1021/cc800106h.

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

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

Daniel M Green et al. J Comb Chem. .

Abstract

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 IC(50) values lower than 100 nM at the GnRH-R.

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