Synthesis and biological evaluation of 3-(2-aminoethyl) uracil derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists

Seon-Mi Kim, Kim SM, 弘三郎 重野, Minhee Lee, Lee M, Lee SY, So Young Lee, Soo-Min Lee, Lee SM, Kim EJ, Eun Jeong Kim, Kim JS, Jae Sun Kim, Ann J, Jihyae Ann, Jiyoun Lee, Lee J, Jeewoo Lee
European Journal of Medicinal Chemistry · 2009 · vol. 22(2) , pp. 154–160 · doi:10.1016/j.ejmech.2017.12.095 · PMID:29335207 · W29335207
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Researchers developed novel uracil analogues and identified compound 12c as a potent GnRH antagonist with prolonged LH suppression in monkeys, showing promise for endometriosis treatment.

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The provided text contains no narrative content, abstract, or full paper body; it consists solely of a title referencing athlete career transitions and a list of biochemical affinity data for GnRH receptor antagonists. Consequently, there are no study populations, methods, or findings to summarize regarding research outcomes. The document appears to be a metadata record or database entry rather than a scholarly article with textual analysis. 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

We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the N-3 aminoethyl side chain and evaluated their antagonistic activity against human gonadotropin-releasing hormone (GnRH) receptors. Analogues with substituents at the ortho or meta position demonstrated potent in vitro antagonistic activity. Specifically, the introduction of a 2-OMe group enhanced nuclear factor of activated T-cells (NFAT) inhibition up to 6-fold compared to the unsubstituted analogue. We identified compound 12c as a highly potent GnRH antagonist with moderate CYP inhibition. Compound 12c showed potent and prolonged LH suppression after a single dose was orally administered in castrated monkeys compared to a known antagonist, Elagolix. We believe that our SAR study offers useful insights to design GnRH antagonists as a potential treatment option for endometriosis.
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Report error Found 52 Enz. Inhib. hit(s) with all data for entry = 50001660 Affinity DataIC50: 0.290nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 0.330nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 0.380nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 0.460nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 0.580nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 0.590nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 0.740nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 1.20nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 1.5nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 1.60nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 2.30nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 3nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 3.5nMAssay Description:Displacement of [125I]D-Trp6-LHRH from monkey GnRH receptor expressed in HEK293 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 3.80nMAssay Description:Displacement of [125I]D-Trp6-LHRH from monkey GnRH receptor expressed in HEK293 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 4.20nMAssay Description:Displacement of [125I]D-Trp6-LHRH from monkey GnRH receptor expressed in HEK293 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 4.90nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 5.40nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 6.20nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 6.30nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 7.5nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 8.40nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 9nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 9nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 11nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 17nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 19nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 32nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 39nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 45nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 46nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 50nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 62nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 65nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 69nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 73nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 89nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 100nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 142nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 144nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 160nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 165nMAssay Description:Antagonist activity at human GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced ...More data for this Ligand-Target Pair Affinity DataIC50: 170nMAssay Description:Antagonist activity at rat GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced NF...More data for this Ligand-Target Pair Affinity DataIC50: 279nMAssay Description:Antagonist activity at rat GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced NF...More data for this Ligand-Target Pair Affinity DataIC50: 590nMAssay Description:Antagonist activity at rat GnRH receptor expressed in HEK293 cells co-expressing pGL4-NFATpromoter AP-1-luc assessed as inhibition of GnRH-induced NF...More data for this Ligand-Target Pair Affinity DataIC50: 1.00E+3nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair Affinity DataIC50: 1.00E+3nMAssay Description:Displacement of [125I]D-Trp6-LHRH from human GnRH receptor expressed in CHO-K1 cells after 1 hr by microbeta scintillation counting methodMore data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Cytochrome P-450 CYP3A Cytochrome P-450 CYP3A Inhibitors Receptors, LHRH Uracil Animals Animals Cytochrome P-450 CYP3A Cytochrome P-450 CYP3A Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 CYP3A Inhibitors Dose-Response Relationship, Drug Dose-Response Relationship, Drug Humans Humans Luteinizing Hormone Luteinizing Hormone Luteinizing Hormone Luteinizing Hormone

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