Discovery of Vilaprisan (BAY1002670): A Highly Potent and Selective Progesterone Receptor Modulator Optimized for Gynecologic Therapies

摘要

Progesterone plays an important role in the femalereproduc- tive system.However,there is also evidence that gynecologic disorders/diseases such as uterine fibroidsand endometriosis are progesterone-dependent. Steroidal and non-steroidal selec- tive progesterone receptor modulators (SPRMs) have shown potentialfor the treatment of such diseases.Steroidal SPRMs, including mifepristone and ulipristal acetate, have provenef- fective in clinical trials. However,several steroidal SPRMs con- taining adimethylamino substituent have been associated with elevated liver enzymes in patients.Anearlier drug discov- ery program identified lonaprisan as ahighly selective SPRM that did not show drug-related change in liver enzyme activity. Buildingondata obtained from that work, here we describe the research program that culminated in the discovery of a novel steroidal SPRM, vilaprisan, whichcombines an extremely high potencywith very favorable drug metabolism andphar- macokinetic properties. Vilaprisan has entered clinical develop- ment and is currentlyundergoing phase 3clinical trials.