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

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.