Synthesis and structure-activity relationships of 2-acylamino-4,6-diphenylpyridine derivatives as novel antagonists of GPR54

Toshitake Kobayashi, Kobayashi T, Satoshi Sasaki, Sasaki S, Tomita N, Naoki Tomita, Fukui S, Seiji Fukui, Kuroda N, Noritaka Kuroda, Masaharu Nakayama, Nakayama M, Atsushi Kiba, Kiba A, Yoshihiro Takatsu, Takatsu Y, Tetsuya Ohtaki, Ohtaki T, Itoh F, Fumio Itoh, Atsuo Baba, Baba A
Bioorganic & medicinal chemistry · 2010 · doi:10.1016/j.bmc.2010.04.036 · PMID:20457527
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Synthesis and structure-activity relationship studies of 2-acylamino-4,6-diphenylpyridine derivatives identified compound 9l as a potent GPR54 antagonist with an IC50 of 3.7 nM, relevant for treating sex-hormone dependent diseases like endometriosis.

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This study synthesized and evaluated a series of 2-acylamino-4,6-diphenylpyridine derivatives to identify novel antagonists targeting the GPR54 receptor. Using CHO cells expressing human GPR54, researchers measured antagonist activity through radioligand displacement assays and calcium mobilization tests, determining IC50 values for each compound. The results established clear structure-activity relationships, with the most potent derivative exhibiting an IC50 of 3.7 nM in displacement assays. 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 has an essential role to modulate sex-hormones including GnRH. Though antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis, small molecule GPR54 antagonists have not been reported. We have synthesized a series of 2-acylamino-4,6-diphenylpyridines to identify potent GPR54 antagonists. Detailed structure-activity relationship studies led to compound 9l with an IC(50) value of 3.7nM in a GPR54 binding assay, and apparent antagonistic activity in a cellular functional assay.
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Description:Displacement of [125I]metastin(40-54) from human GPR54 receptor expressed in CHO cells after 60 mins by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 460nMAssay Description:Antagonist activity at human GPR54 receptor expressed in CHO cells assessed as inhibition of metastin(40-54)-induced intracellular calcium mobilizati...More data for this Ligand-Target Pair Affinity DataIC50: 480nMAssay Description:Displacement of [125I]metastin(40-54) from human GPR54 receptor expressed in CHO cells after 60 mins by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 490nMAssay Description:Displacement of [125I]metastin(40-54) from human GPR54 receptor expressed in CHO cells after 60 mins by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 570nMAssay Description:Displacement of [125I]metastin(40-54) from human GPR54 receptor expressed in CHO cells after 60 mins by scintillation countingMore data 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mobilizati...More data for this Ligand-Target Pair Affinity DataIC50: 2.80E+3nMAssay Description:Antagonist activity at human GPR54 receptor expressed in CHO cells assessed as inhibition of metastin(40-54)-induced intracellular calcium mobilizati...More data for this Ligand-Target Pair Affinity DataIC50: 3.60E+3nMAssay Description:Antagonist activity at human GPR54 receptor expressed in CHO cells assessed as inhibition of metastin(40-54)-induced intracellular calcium mobilizati...More data for this Ligand-Target Pair Affinity DataIC50: 4.10E+3nMAssay Description:Antagonist activity at human GPR54 receptor expressed in CHO cells assessed as inhibition of metastin(40-54)-induced intracellular calcium mobilizati...More data for this Ligand-Target Pair Affinity DataIC50: 5.10E+3nMAssay Description:Antagonist activity at human GPR54 receptor expressed in CHO cells assessed as inhibition of metastin(40-54)-induced intracellular calcium mobilizati...More data for this Ligand-Target Pair Affinity DataIC50: 6.30E+3nMAssay Description:Antagonist activity at human GPR54 receptor expressed in CHO cells assessed as inhibition of metastin(40-54)-induced intracellular calcium mobilizati...More data for this Ligand-Target Pair Affinity DataIC50: 9.90E+3nMAssay Description:Displacement of [125I]metastin(40-54) from human GPR54 receptor expressed in CHO cells after 60 mins by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 2.40E+4nMAssay Description:Antagonist activity at human GPR54 receptor expressed in CHO cells assessed as inhibition of metastin(40-54)-induced intracellular calcium mobilizati...More data for this Ligand-Target Pair Affinity DataIC50: 3.00E+4nMAssay Description:Displacement of [125I]metastin(40-54) from human GPR54 receptor expressed in CHO cells after 60 mins by scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 3.30E+4nMAssay Description:Displacement of [125I]metastin(40-54) from human GPR54 receptor expressed in CHO cells after 60 mins by scintillation countingMore data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Pyridines Pyridines Receptors, G-Protein-Coupled Animals CHO Cells Cricetinae Cricetulus Humans Inhibitory Concentration 50 Pyridines Pyridines Receptors, G-Protein-Coupled Receptors, G-Protein-Coupled Receptors, Kisspeptin-1 Structure-Activity Relationship

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europepmc
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pubmed
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