2. Academic Validation
  3. 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

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

  • J Med Chem. 2019 Nov 27;62(22):10321-10341. doi: 10.1021/acs.jmedchem.9b01382.
Lars Wortmann 1,  Bernhard Lindenthal 1,  Peter Muhn 1,  Alexander Walter 1,  Reinhard Nubbemeyer 1,  Dieter Heldmann 1,  Lothar Sobek 1,  Federica Morandi 2,  Anna K Schrey 2,  Dieter Moosmayer 1,  Judith Günther 1,  Joachim Kuhnke 1,  Marcus Koppitz 1,  Ulrich Lücking 1,  Ulrike Röhn 1,  Martina Schäfer 1,  Katrin Nowak-Reppel 1,  Ronald Kühne 2,  Hilmar Weinmann 1,  Gernot Langer 1
Affiliations

Affiliations

  • 1 Bayer AG, Research & Development, Pharmaceuticals , 13353 Berlin , Germany.
  • 2 Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) , Robert-Rössle Strasse 10 , Campus Berlin-Buch, 13125 Berlin , Germany.
PMID: 31670515 DOI: 10.1021/acs.jmedchem.9b01382
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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