Open AccessDiscovery and Characterization of BAY 1214784, an Orally Available Spiroindoline Derivative Acting as a Potent and Selective Antagonist of the Human Gonadotropin-Releasing Hormone Receptor as Proven in a First-In-Human Study in Postmenopausal Women
Author(s) -
Olaf Panknin,
Andrea Wagenfeld,
Wilhelm Bone,
Eckhard Bender,
Katrin Nowak-Reppel,
Amaury E Fernández-Montalván,
Reinhard Nubbemeyer,
Stefan Bäurle,
Sven Ring,
Norbert Schmees,
Olaf Prien,
Martina Schäfer,
Christian Friedrich,
Thomas M. Zollner,
Andreas Steinmeyer,
Thomas Mueller,
Gernot Langer
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01076
Subject(s) - antagonist , hormone , luteinizing hormone , chemistry , gonadotropin releasing hormone receptor , estrogen , pharmacology , hormone receptor , endocrinology , medicine , tolerability , estrogen receptor , receptor , gonadotropin releasing hormone , adverse effect , cancer , breast cancer
The growth of uterine fibroids is sex hormone-dependent and commonly associated with highly incapacitating symptoms. Most treatment options consist of the control of these hormonal effects, ultimately blocking proliferative estrogen signaling ( i.e. , oral contraceptives/antagonization of human gonadotropin-releasing hormone receptor [hGnRH-R] activity). Full hGnRH-R blockade, however, results in menopausal symptoms and affects bone mineralization, thus limiting treatment duration or demanding estrogen add-back approaches. To overcome such issues, we aimed to identify novel, small-molecule hGnRH-R antagonists. This led to the discovery of compound BAY 1214784, an orally available, potent, and selective hGnRH-R antagonist. Altering the geminal dimethylindoline core of the initial hit compound to a spiroindoline system significantly improved GnRH-R antagonist potencies across several species, mandatory for a successful compound optimization in vivo . In a first-in-human study in postmenopausal women, once daily treatment with BAY 1214784 effectively lowered plasma luteinizing hormone levels by up to 49%, at the same time being associated with low pharmacokinetic variability and good tolerability.