vilaprisan and Genital-Diseases--Female

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.

Topics: Animals; Cell Line, Tumor; Drug Discovery; Estrenes; Female; Genital Diseases, Female; Humans; Leiomyoma; Molecular Structure; Pregnancy; Rabbits; Rats, Wistar; Receptors, Progesterone; Steroids; Structure-Activity Relationship

Does the novel progesterone receptor (PR) modulator BAY 1002670, based on its preclinical pharmacological profile, offer a potential novel treatment option for uterine fibroids?. The newly synthesized BAY1002670 has proved to be a very potent, highly selective PR modulator in all in vitro and in vivo pharmacodynamics assays performed: it exhibits marked efficacy in an innovative humanized fibroid disease model, suggesting BAY 1002670 to be a very promising treatment option for uterine fibroids.. PR inhibiting ligands have shown clinical utility in a range of potential indications and applications. Despite the emergence of the first PR antagonist >30 years ago, no agent of this compound class has been authorized in any indication for long-term application. Among other reasons, suboptimal selectivity and safety profiles of previous candidates have led to discontinuation and modification of development programmes.. The preclinical studies include relevant in vitro and in vivo assays to clarify the properties of the PR modulator BAY 1002670 as well as a fibroid xenograft study to show directly the efficacy of BAY 1002670 on the human target tissue.. BAY 1002670 was tested for binding and transactivational activity towards different human steroid receptors. Activity of the compound in the corresponding in vivo models (rat, rabbit) was assessed. Furthermore, BAY 1002670 was tested in a disease model for uterine fibroids utilizing primary human tumour tissues as xenograft in immunodeficient mice treated with estradiol (E2) and progesterone (P).. BAY1002670 in subnanomolar concentrations exhibits a highly selective binding profile and antagonistic activity for the PR. These properties are also reflected in its action in two progesterone-dependent animal models that assess the termination of pregnancy and endometrial transformation. Favourable selectivity towards other nuclear hormone receptors was demonstrated. No in vivo activity was found at the glucocorticoid, estrogenic and mineralocorticoid receptors with only weak anti-androgenic activity. In a human fibroid xenograft model BAY 1002670 showed a marked dose-dependent reduction of fibroid tumour weight gain of 95% at a dose of 3 mg/kg/day (P < 0.005).. Selectivity and potency of BAY 1002670 have only been determined in vitro and in animal models so far.. The PR modulator BAY 1002670 might offer a treatment option not only for uterine fibroids but also for other gynaecological indications.. The studies took place at Bayer Pharma AG. All authors are employees of Bayer Pharma AG. No external funding declared.

Topics: Animals; Estradiol; Female; Genital Diseases, Female; Heterografts; Humans; Leiomyoma; Mice; Progesterone; Rabbits; Rats; Receptors, Progesterone; Steroids; Transcriptional Activation