2-phenyl-4-piperazinylbenzimidazoles: orally active inhibitors of the gonadotropin releasing hormone (GnRH) receptor

Jeffrey C Pelletier, Murty Chengalvala, Josh Cottom, Irene Feingold, Lloyd Garrick, Daniel Green, Diane Hauze, Christine Huselton, James Jetter, Wenling Kao, Gregory S Kopf, Joseph T Lundquist, Charles Mann, John Mehlmann, John Rogers, Linda Shanno, Jay Wrobel
Bioorganic & medicinal chemistry · 2008 · doi:10.1016/j.bmc.2008.05.024 · PMID:18511284
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⚙ AI-generated summary by claude@2026-06, 2026-06-11 ⓘ

This study describes the discovery of 2-phenyl-4-piperazinylbenzimidazoles as orally active small molecule GnRH receptor antagonists with nanomolar potency and significant LH suppression in rats.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-11 · read from full text ⓘ

The paper reports the identification and characterization of orally active 2-phenyl-4-piperazinylbenzimidazole compounds as inhibitors/antagonists of the human and rat gonadotropin-releasing hormone (GnRH) receptor, with binding tested via displacement of radiolabeled (D-Trp6)LHRH and functional antagonism assessed by reduction of (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol production and inhibition of LH release in CO2-asphyxiated rat primary pituitary cells. Across assays, reported potency values span from low nanomolar to much higher concentrations for displacement and antagonist effects, and some compounds also show binding affinity to serotonin receptor subtypes (e.g., 5HT1A/5HT1B/5HT2A). A stated limitation is that only in vitro/recombinant-receptor and primary pituitary cell assay outcomes are provided in the supplied text, without detailed in vivo efficacy, selectivity quantification, or safety data. Relevance to endometriosis: this work focuses on GnRH receptor antagonists and does not explicitly discuss endometriosis or adenomyosis in the provided text, so it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Antagonism of the gonadotropin releasing hormone (GnRH) receptor has shown positive clinical results in numerous reproductive tissue disorders such as endometriosis, prostate cancer and others. Traditional therapy has been limited to peptide agonists and antagonists. Recently, small molecule GnRH antagonists have emerged as potentially new treatments. This article describes the discovery of 2-phenyl-4-piperazinylbenzimidazoles as small molecule GnRH antagonists with nanomolar potency in in vitro binding and functional assays, excellent bioavailability (rat %F>70) and demonstrated oral activity in a rat model having shown significant serum leuteinizing hormone (LH) suppression.
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Report error Found 64 Enz. Inhib. hit(s) with all data for entry = 50026227 Affinity DataKi: 0.550nMAssay Description:Binding affinity to human 5HT1D receptorMore data for this Ligand-Target Pair Affinity DataIC50: 1.70nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 2.30nMAssay Description:Binding affinity to human 5HT1A receptorMore data for this Ligand-Target Pair Affinity DataKi: 2.80nMAssay Description:Binding affinity to human 5HT1A receptorMore data for this Ligand-Target Pair Affinity DataIC50: 4nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 4.90nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 5.5nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 5.70nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 6.20nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 8.70nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 9.40nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 11nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 14nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 17.5nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from rat recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataKi: 19nMAssay Description:Binding affinity to human 5HT1A receptorMore data for this Ligand-Target Pair Affinity DataIC50: 24nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 25nMAssay Description:Antagonist activity at recombinant GnRH receptor in CO2 asphyxiated rat primary pituitary cells assessed as reduction in (D-Trp6)LHRH-induced LH rele...More data for this Ligand-Target Pair Affinity DataIC50: 32nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from rat recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 40nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from rat recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 41nMAssay Description:Antagonist activity at recombinant GnRH receptor in CO2 asphyxiated rat primary pituitary cells assessed as reduction in (D-Trp6)LHRH-induced LH rele...More data for this Ligand-Target Pair Affinity DataIC50: 50nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 59nMAssay Description:Antagonist activity at recombinant GnRH receptor in CO2 asphyxiated rat primary pituitary cells assessed as reduction in (D-Trp6)LHRH-induced LH rele...More data for this Ligand-Target Pair Affinity DataKi: 60nMAssay Description:Binding affinity to human 5HT1B receptorMore data for this Ligand-Target Pair Affinity DataIC50: 63nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 72nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from rat recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 110nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from rat recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 120nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 120nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 220nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataKi: 230nMAssay Description:Binding affinity to 5HT2A receptorMore data for this Ligand-Target Pair Affinity DataIC50: 240nMAssay Description:Antagonist activity at recombinant GnRH receptor in CO2 asphyxiated rat primary pituitary cells assessed as reduction in (D-Trp6)LHRH-induced LH rele...More data for this Ligand-Target Pair Affinity DataIC50: 450nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 480nMAssay Description:Antagonist activity at recombinant GnRH receptor in CO2 asphyxiated rat primary pituitary cells assessed as reduction in (D-Trp6)LHRH-induced LH rele...More data for this Ligand-Target Pair Affinity DataIC50: 580nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 640nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 680nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from rat recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 710nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from rat recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 790nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 990nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from rat recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 1.20E+3nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 1.20E+3nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 1.30E+3nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 1.50E+3nMAssay Description:Antagonist activity at recombinant GnRH receptor in CO2 asphyxiated rat primary pituitary cells assessed as reduction in (D-Trp6)LHRH-induced LH rele...More data for this Ligand-Target Pair Affinity DataIC50: 1.50E+3nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 2.30E+3nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 2.80E+3nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 3.30E+3nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 3.40E+3nMAssay Description:Antagonist activity at human recombinant GnRH receptor assessed as reduction in (D-Trp6)LHRH-induced myo-(1,2)-[3H]inositol productionMore data for this Ligand-Target Pair Affinity DataIC50: 3.90E+3nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from rat recombinant GnRH receptorMore data for this Ligand-Target Pair Affinity DataIC50: 4.50E+3nMAssay Description:Displacement of [125I]-(D-Trp6)LHRH from human recombinant GnRH receptorMore data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Benzimidazoles Benzimidazoles Piperazines Receptors, LHRH Administration, Oral Animals Benzimidazoles Benzimidazoles Cross-Linking Reagents Cross-Linking Reagents Glycolates Glycolates Humans Luteinizing Hormone Luteinizing Hormone Male Methylation Molecular Structure Piperazine Piperazines

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europepmc
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