Discovery of Vilaprisan (BAY 1002670): A Highly Potent and Selective Progesterone Receptor Modulator Optimized for Gynecologic Therapies. (8th November 2018)

• Record Type: Journal Article
• Authors: Möller, Carsten; Bone, Wilhelm; Cleve, Arwed; Klar, Ulrich; Rotgeri, Andrea; Rottmann, Antje; Schultze‐Mosgau, Marcus‐Hillert; Wagenfeld, Andrea; Schwede, Wolfgang
• Is Part Of: ChemMedChem. Volume 13:Number 21(2018)
• Page Start: 2271
• Page End: 2280
• Publication Date: 2018-11-08
• Subjects: fluorinated ligands -- gynecologic therapies -- methyl sulfone -- selective progesterone receptor modulator -- structure–activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800487
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone‐dependent. Steroidal and non‐steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the treatment of such diseases. Steroidal SPRMs, including mifepristone and ulipristal acetate, have proven effective in clinical trials. However, several steroidal SPRMs containing a dimethylamino substituent have been associated with elevated liver enzymes in patients. An earlier drug discovery program identified lonaprisan as a highly selective SPRM that did not show drug‐related change in liver enzyme activity. Building on data obtained from that work, here we describe the research program that culminated in the discovery of a novel steroidal SPRM, vilaprisan, which combines an extremely high potency with very favorable drug metabolism and pharmacokinetic properties. Vilaprisan has entered clinical development and is currently undergoing phase 3 clinical trials. Abstract : Good PR : The discovery of vilaprisan, a highly selective progesterone receptor (PR) modulator, is described. Compared with other candidates, vilaprisan shows unique selectivity combined with improved drug metabolism and pharmacokinetic profile. Vilaprisan is in advanced clinical trials for the treatment of gynecologic diseases with high unmet medical need. Vilaprisan modeled into the ligand‐binding site of the PR.