title: Parallel synthesis of 2-aryl-4-aminobenzimidazoles and their evaluation as gonadotropin releasing hormone antagonists.
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.
authors.affiliation: Department of Chemical and Screeing Sciences, Wyeth Research, Collegeville, Pennsylvania 19426, USA. greend@wyeth.com
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Green
authors.forename: Igor
authors.initials: I
authors.lastname: Goljer
authors.forename: Diane S
authors.initials: DS
authors.lastname: Andraka
authors.forename: Murty
authors.initials: M
authors.lastname: Chengalvala
authors.forename: Linda
authors.initials: L
authors.lastname: Shanno
authors.forename: Warren
authors.initials: W
authors.lastname: Hurlburt
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Pelletier
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D003959:Diamines / Q000737:chemistry; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D054852:Small Molecule Libraries / Q000138:chemical synthesis; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D002264:Carboxylic Acids; D003959:Diamines; D006727:Hormone Antagonists; D054852:Small Molecule Libraries; D007987:Gonadotropin-Releasing Hormone