2-acylamino-4,6-diphenylpyridine derivatives as novel GPR54 antagonists with good brain exposure and in vivo efficacy for plasma LH level in male rats

Toshitake Kobayashi, Kobayashi T, Satoshi Sasaki, Sasaki S, Naoki Tomita, Tomita N, Fukui S, Seiji Fukui, Masaharu Nakayama, Nakayama M, Kiba A, Atsushi Kiba, Kusaka M, Masami Kusaka, Shin-ichi Matsumoto, Matsumoto S, Yamaguchi M, Masashi Yamaguchi, Itoh F, Fumio Itoh, Baba A, Atsuo Baba
Bioorganic & medicinal chemistry · 2010 · doi:10.1016/j.bmc.2010.05.061 · PMID:20580563
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⚙ AI-generated summary by claude@2026-07, 2026-07-09 ⓘ

Researchers developed novel 2-acylamino-4,6-diphenylpyridine derivatives that act as GPR54 antagonists with improved brain exposure and in vivo efficacy in suppressing plasma LH levels in male rats.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-09 · read from full text ⓘ

This paper reports the identification and characterization of 2-acylamino-4,6-diphenylpyridine derivatives as antagonists of the GPR54 (Kisspeptin receptor), evaluating their binding in cell-based displacement assays using CHO cells expressing human or rat GPR54. The compounds showed low nanomolar to high nanomolar antagonist potency in displacing [125I]metastin (IC50 values ranging from about 3–30 nM for several entries, with weaker entries extending to much higher values), and antagonist activity was also assessed by inhibition of metastin-induced calcium mobilization, including a poorly potent example with IC50 values up to ~930 nM. The authors further claim good brain exposure and in vivo efficacy for lowering plasma LH levels in male rats, though the provided text does not include the quantitative in vivo dosing or effect sizes. The 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

GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor plays an essential role to modulate sex-hormones including GnRH. Thus, antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis. We recently reported 2-acylamino-4,6-diphenylpyridines as the first small molecule GPR54 antagonists with high potency. However, the representative compound 1 showed low brain exposure, where GPR54 acts as a modulator of gonadotropins by binding with its endogenous ligand, metastin. In order to discover compounds that have not only potent GPR54 antagonistic activity but also good brain permeability, we focused on converting the primary amine on the side chain to a secondary or tertiary amine, and finally we identified 15a containing a piperazine group. This compound exhibited high affinity to human and rat GPR54, apparent antagonistic activity, and high brain exposure. In addition, intravenous administration of 15a to castrated male rat suppressed plasma LH level, which indicates the possibility of a small molecule GPR54 antagonist as a novel drug for sex-hormone dependent diseases.
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Report error Found 42 Enz. Inhib. hit(s) with all data for entry = 50039236 Affinity DataIC50: 3.60nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 3.70nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 4.10nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 4.60nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 7.30nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 7.40nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 7.90nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 8nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 8.40nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 9.70nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 9.70nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 11nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 12nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 14nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Displacement of [125I]metastin from rat GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 17nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Displacement of [125I]metastin from rat GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 25nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 26nMAssay Description:Displacement of [125I]metastin from rat GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 26nMAssay Description:Displacement of [125I]metastin from rat GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 30nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 30nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 38nMAssay Description:Displacement of [125I]metastin from rat GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 47nMAssay Description:Displacement of [125I]metastin from rat GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 47nMAssay Description:Displacement of [125I]metastin from rat GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 130nMAssay Description:Displacement of [125I]metastin from rat GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 180nMAssay Description:Displacement of [125I]metastin from human GPR54 receptor expressed in CHO cellsMore data for this Ligand-Target Pair Affinity DataIC50: 930nMAssay Description:Antagonist activity at human GPR54 receptor assessed as inhibition of metastin-induced calcium mobilizationMore data for this Ligand-Target Pair

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endometriosis

MeSH descriptors

Aminopyridines Aminopyridines Brain Luteinizing Hormone Receptors, G-Protein-Coupled Aminopyridines Animals Brain Caco-2 Cells CHO Cells Cricetinae Cricetulus Humans Luteinizing Hormone Luteinizing Hormone Male Rats Rats, Wistar Receptors, G-Protein-Coupled Receptors, G-Protein-Coupled

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