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

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.

A Facile Three‐Component Catalyst‐Free Strategy: Synthesis of Indeno[1,2‐b][1,6]naphthyridine‐1,10(2H)‐dione Derivatives in Water

“…The product was obtained only with 60% yield when acetic acid was used as solvent (entry 8). A slight improvement was observed when DMF, glycol, or ethanol was used as the solvent respectively in the absence of acidic catalyst (entries [9][10][11]. In order to further optimize the experimental conditions, the three-component domino reaction was examined under different reaction temperatures.…”

“…[8] The BAY-298 (III) which showed potent antagonism for LH-R in humans, rats and cynomolgus monkeys, has been studied as the first nanomolar hLH-R antagonist to reduce sex hormone levels in vivo. [9] The 5,6,7,8tetrahydro-1,6-naphthyridine derivatives (IV), targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/ p75)-binding site on HIV-1 integrase, showed activity against HIV-1 infection in cell culture. [10] Owing to their interesting properties, the development of a facile protocol for the direct formation of biological highly substituted 1,6-naphthyridine derivatives is an important and promising subject.…”

“…Compounds ( II ) and their analogues displayed antiproliferative activity against four human cancer cell lines [8] . The BAY‐298 ( III ) which showed potent antagonism for LH‐R in humans, rats and cynomolgus monkeys, has been studied as the first nanomolar hLH‐R antagonist to reduce sex hormone levels in vivo [9] . The 5,6,7,8‐tetrahydro‐1,6‐naphthyridine derivatives ( IV ), targeting the allosteric lens‐epithelium‐derived‐growth‐factor‐p75 (LEDGF/p75)‐binding site on HIV‐1 integrase, showed activity against HIV‐1 infection in cell culture [10] .…”

Discovery and Characterization of the Potent and Highly Selective 1,7-Naphthyridine-Based Inhibitors BAY-091 and BAY-297 of the Kinase PIP4K2A

“…The less active enantiomer (data not shown) can be used as a negative control. Once accepted, Bayer probe molecules (soon including PIP4K2A probe BAY-091) − can be ordered for free via the SGC website…”

Development of A Recombinant Murine Luteinizing Hormone Binding Protein As A Selective Hormone Inhibitor

“…A peptide to inhibit the binding of FSH to its receptor and an anti-FSH beta monoclonal antibody have been reported to suppress FSH actions in vivo in mice 9,10 . As a selective LH inhibitor, BAY-298, a small-molecule allosteric modulator for the LH receptor, has been reported, but this inhibitor does not act on mouse LH receptors 11 .…”