Synthesis and biological evaluation of piperazinyl heterocyclic antagonists of the gonadotropin releasing hormone (GnRH) receptor

Matthew D Vera, Vera MD, Lundquist JT 4th, Joseph T Lundquist, Murty V Chengalvala, Chengalvala MV, Cottom JE, Joshua E Cottom, Irene B Feingold, Feingold IB, Lloyd M Garrick, Garrick LM, Green DM, Daniel M Green, Hauze DB, Diane B Hauze, Charles W Mann, Mann CW, John F Mehlmann, Mehlmann JF, Rogers JF, John F Rogers, Linda Shanno, Shanno L, Wrobel JE, Jay E Wrobel, Jeffrey C Pelletier, Pelletier JC
Bioorganic & medicinal chemistry letters · 2010 · doi:10.1016/j.bmcl.2010.02.099 · PMID:20236823
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⚙ AI-generated summary by claude@2026-06, 2026-06-13 ⓘ

This study synthesized and evaluated novel piperazinyl heterocyclic compounds, with the imidazopyridine scaffold demonstrating nanomolar binding potency and functional antagonism at GnRH receptors.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-13 · read from full text ⓘ

The paper reports the synthesis and biological evaluation of piperazinyl heterocyclic gonadotropin-releasing hormone (GnRH) receptor antagonists, assessing their ability to inhibit GnRH receptor activation. Antagonist potency was measured using displacement of [125I]D-Trp6-GnRH from human or rat recombinant GnRH receptors and inhibition of D-Trp6-GnRH–induced IP accumulation (1 hr) or LH accumulation in rat pituitary cells (3 hr), producing a wide range of reported IC50 values. A key limitation is that the provided text mainly contains affinity/functional IC50 readouts without detailed methods, chemical structures, or the rationale linking specific compounds to activity trends. This paper does not explicitly discuss endometriosis or adenomyosis; 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 resulted in positive clinical results in reproductive tissue disorders such as endometriosis and prostate cancer. Following the recent discovery of orally active GnRH antagonists based on a 4-piperazinylbenzimidazole template, we sought to investigate the properties of heterocyclic isosteres of the benzimidazole template. We report here the synthesis and biological activity of eight novel scaffolds, including imidazopyridines, benzothiazoles and benzoxazoles. The 2-(4-tert-butylphenyl)-8-(piperazin-1-yl)imidazo[1,2-a]pyridine ring system was shown to have nanomolar binding potency at the human and rat GnRH receptors as well as functional antagonism in vitro. Additional structure-activity relationships within this series are reported along with a pharmacokinetic comparison to the benzimidazole-based lead molecule.
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Report error Found 41 Enz. Inhib. hit(s) with all data for entry = 50031555 Affinity DataIC50: 2.30nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 4.30nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 5nMAssay Description:Antagonist activity at human recombinant GNRH receptor assessed as inhibition of D-Trp6-GNRH-induced IP accumulation after 1 hr by rapid filtration a...More data for this Ligand-Target Pair Affinity DataIC50: 5.70nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 5.80nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 6.70nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 9.80nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 12nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 12nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Antagonist activity at human recombinant GNRH receptor assessed as inhibition of D-Trp6-GNRH-induced IP accumulation after 1 hr by rapid filtration a...More data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Antagonist activity at human recombinant GNRH receptor assessed as inhibition of D-Trp6-GNRH-induced IP accumulation after 1 hr by rapid filtration a...More data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Antagonist activity at human recombinant GNRH receptor assessed as inhibition of D-Trp6-GNRH-induced IP accumulation after 1 hr by rapid filtration a...More data for this Ligand-Target Pair Affinity DataIC50: 24nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 28nMAssay Description:Antagonist activity at human recombinant GNRH receptor assessed as inhibition of D-Trp6-GNRH-induced IP accumulation after 1 hr by rapid filtration a...More data for this Ligand-Target Pair Affinity DataIC50: 29nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 34nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 37nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 39nMAssay Description:Antagonist activity at human recombinant GNRH receptor assessed as inhibition of D-Trp6-GNRH-induced IP accumulation after 1 hr by rapid filtration a...More data for this Ligand-Target Pair Affinity DataIC50: 41nMAssay Description:Antagonist activity at human recombinant GNRH receptor assessed as inhibition of D-Trp6-GNRH-induced IP accumulation after 1 hr by rapid filtration a...More data for this Ligand-Target Pair Affinity DataIC50: 44nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 47nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 58nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 60nMAssay Description:Antagonist activity at human recombinant GNRH receptor assessed as inhibition of D-Trp6-GNRH-induced IP accumulation after 1 hr by rapid filtration a...More data for this Ligand-Target Pair Affinity DataIC50: 72nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 81nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 90nMAssay Description:Antagonist activity at human recombinant GNRH receptor assessed as inhibition of D-Trp6-GNRH-induced IP accumulation after 1 hr by rapid filtration a...More data for this Ligand-Target Pair Affinity DataIC50: 95nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 160nMAssay Description:Antagonist activity at GNRH receptor in rat pituitary cells assessed as inhibition of D-Trp6-GnRH-induced LH accumulation after 3 hrs by RIAMore data for this Ligand-Target Pair Affinity DataIC50: 200nMAssay Description:Antagonist activity at GNRH receptor in rat pituitary cells assessed as inhibition of D-Trp6-GnRH-induced LH accumulation after 3 hrs by RIAMore data for this Ligand-Target Pair Affinity DataIC50: 260nMAssay Description:Antagonist activity at GNRH receptor in rat pituitary cells assessed as inhibition of D-Trp6-GnRH-induced LH accumulation after 3 hrs by RIAMore data for this Ligand-Target Pair Affinity DataIC50: 290nMAssay Description:Displacement of [125I]D-Trp6-GnRH from rat recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 360nMAssay Description:Antagonist activity at GNRH receptor in rat pituitary cells assessed as inhibition of D-Trp6-GnRH-induced LH accumulation after 3 hrs by RIAMore data for this Ligand-Target Pair Affinity DataIC50: 420nMAssay Description:Antagonist activity at GNRH receptor in rat pituitary cells assessed as inhibition of D-Trp6-GnRH-induced LH accumulation after 3 hrs by RIAMore data for this Ligand-Target Pair Affinity DataIC50: 920nMAssay Description:Antagonist activity at GNRH receptor in rat pituitary cells assessed as inhibition of D-Trp6-GnRH-induced LH accumulation after 3 hrs by RIAMore data for this Ligand-Target Pair Affinity DataIC50: 1.50E+3nMAssay Description:Antagonist activity at GNRH receptor in rat pituitary cells assessed as inhibition of D-Trp6-GnRH-induced LH accumulation after 3 hrs by RIAMore data for this Ligand-Target Pair Affinity DataIC50: 3.40E+3nMAssay Description:Antagonist activity at GNRH receptor in rat pituitary cells assessed as inhibition of D-Trp6-GnRH-induced LH accumulation after 3 hrs by RIAMore data for this Ligand-Target Pair Affinity DataIC50: 4.40E+3nMAssay Description:Antagonist activity at GNRH receptor in rat pituitary cells assessed as inhibition of D-Trp6-GnRH-induced LH accumulation after 3 hrs by RIAMore data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 1.00E+4nMAssay Description:Displacement of [125I]D-Trp6-GnRH from human recombinant GNRH receptor by scintillation countingMore data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Heterocyclic Compounds Heterocyclic Compounds Piperazines Piperazines Receptors, LHRH Animals Biological Availability Cells, Cultured Half-Life Heterocyclic Compounds Heterocyclic Compounds Humans Male Piperazines Piperazines Rats Rats, Sprague-Dawley Receptors, LHRH

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