Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-Based, Potent, and Selective Antagonists of the Luteinizing Hormone Receptor Which Reduce Sex Hormone Levels in Vivo

Lars Wortmann, Bernhard Lindenthal, Lindenthal B, Peter Muhn, Muhn P, Walter A, Alexander Walter, Reinhard Nubbemeyer, Nubbemeyer R, Heldmann D, Dieter Heldmann, Lothar Sobek, Sobek L, Federica Morandi, Morandi F, Schrey AK, Anna K Schrey, Moosmayer D, Dieter Moosmayer, Judith Günther, Günther J, Kuhnke J, Joachim Kuhnke, Koppitz M, Marcus Koppitz, Lücking U, Ulrich Lücking, Röhn U, Ulrike Röhn, Martina Schäfer, Schäfer M, Katrin Nowak-Reppel, Nowak-Reppel K, Ronald Kühne, Kühne R, Weinmann H, Hilmar Weinmann, Gernot Langer, Langer G
Journal of medicinal chemistry · 2019 · doi:10.1021/acs.jmedchem.9b01382 · PMID:31670515
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BAY-298 and BAY-899 are novel, selective tetrahydro-1,6-naphthyridine-based antagonists of the luteinizing hormone receptor that reduce sex hormone levels in vivo.

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The paper reports the discovery and characterization of BAY-298 and BAY-899, tetrahydro-1,6-naphthyridine-based antagonists of the luteinizing hormone receptor, and evaluates their ability to reduce sex hormone levels in vivo. High-level potency and selectivity are assessed using in vitro assays including human liver microsome CYP inhibition and functional inhibition of human ERG expressed in HEK293 cells via whole-cell voltage-clamp, with reported IC50 values in the nanomolar to tens-of-micromolar range across tested targets. The provided text mainly contains affinity/IC50 screening outputs without detailed experimental context or in-depth biological results, limiting interpretation of the overall mechanism and selectivity profile. 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

The human luteinizing hormone receptor (hLH-R) is a member of the glycoprotein hormone family of G-protein-coupled receptors (GPCRs), activated by luteinizing hormone (hLH) and essentially involved in the regulation of sex hormone production. Thus, hLH-R represents a valid target for the treatment of sex hormone-dependent cancers and diseases (polycystic ovary syndrome, uterine fibroids, endometriosis) as well as contraception. Screening of the Bayer compound library led to the discovery of tetrahydrothienopyridine derivatives as novel, small-molecule (SMOL) hLH-R inhibitors and to the development of BAY-298, the first nanomolar hLH-R antagonist reducing sex hormone levels in vivo. Further optimization of physicochemical, pharmacokinetic, and safety parameters led to the identification of BAY-899 with an improved in vitro profile and proven efficacy in vivo. BAY-298 and BAY-899 serve as valuable tool compounds to study hLH-R signaling in vitro and to interfere with the production of sex hormones in vivo.
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Report error Found 14 Enz. Inhib. hit(s) with all data for entry = 50007060 Affinity DataIC50: 700nMAssay Description:Inhibition of CYP2C8 in human liver microsomes using amodiaquine as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 3.00E+3nMAssay Description:Inhibition of human ERG expressed in HEK293 cells at holding potential -80 mV by whole-cell voltage-clamp methodMore data for this Ligand-Target Pair Affinity DataIC50: 3.10E+3nMAssay Description:Inhibition of CYP2C8 in human liver microsomes using amodiaquine as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 4.40E+3nMAssay Description:Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 9.90E+3nMAssay Description:Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 1.06E+4nMAssay Description:Inhibition of human ERG expressed in HEK293 cells at holding potential -80 mV by whole-cell voltage-clamp methodMore data for this Ligand-Target Pair Affinity DataIC50: 2.00E+4nMAssay Description:Inhibition of CYP3A4 in human liver microsomes using midazolam as substrate treated prior to substrate addition by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.00E+4nMAssay Description:Inhibition of CYP1A2 in human liver microsomes using phenacetin as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.00E+4nMAssay Description:Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.00E+4nMAssay Description:Inhibition of CYP3A4 in human liver microsomes using midazolam as substrate treated prior to substrate addition by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.00E+4nMAssay Description:Inhibition of CYP3A4 in human liver microsomes using midazolam as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.00E+4nMAssay Description:Inhibition of CYP3A4 in human liver microsomes using midazolam as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.00E+4nMAssay Description:Inhibition of CYP2D6 in human liver microsomes using dextromethorphan as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair Affinity DataIC50: 2.00E+4nMAssay Description:Inhibition of CYP1A2 in human liver microsomes using phenacetin as substrate by LC-MS/MS analysisMore data for this Ligand-Target Pair

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endometriosis

MeSH descriptors

Estradiol Naphthyridines Receptors, LH Administration, Oral Animals Biological Availability Dose-Response Relationship, Drug ERG1 Potassium Channel ERG1 Potassium Channel Estradiol Female Granulosa Cells Granulosa Cells High-Throughput Screening Assays Humans Male Mice Microsomes, Liver Microsomes, Liver Naphthyridines

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