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

摘要

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.