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

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.

Keywords: fluorinated ligands; gynecologic therapies; methyl sulfone; selective progesterone receptor modulator; structure-activity relationships.

Scheme 1

Clinically tested progesterone receptor modulators.

Scheme 2

Vilaprisan and its human plasma metabolites.

Scheme 3

General synthetic approach: a) C₂F₅I, MeLi‐LiBr, −70 °C then 0 °C; b) phenyl Grignard, cat. CuCl, THF, 0 °C; for compound 24 l: iso‐propylmagnesium chloride, nBuLi, 3‐(4‐bromophenyl)‐3‐methyloxetane, cat. CuCl, THF, 0 °C; c) acidic cleavage.

Scheme 4

Synthesis of derivatives that require additional modification of Y′: a) diazomethane, Pd(OAc)₂, Et₂O, 0 °C; b) 2 n HCl, acetone, RT; c) acetic acid, 35 °C; d) Jones reagent, 0 °C; e) TBTU, methylamine, RT; f) TBAF, THF, RT; g) TPAP, NMO, CH₂Cl₂, molecular sieves, RT; h) 2‐methyl‐2‐butene, THF, tBuOH, NaOCl, 0 °C; i) (trimethylsilyl)diazomethane, THF, RT; j) NH₃ in methanol, 85 °C; k) sulfuric acid, methanol, RT; l) oxone, 0 °C, m) amine, sodium triacetoxyborohydride, CH₂Cl₂, RT.

Scheme 5

Synthesis of the biphenylcarboxylic acid 11: a) ammonium formate, Pd/C, methanol, RT; b) C₄F₉SO₂F, nBuLi, THF, 0 °C; c) [4‐(methoxycarbonyl)phenyl]boronic acid, Pd(PPh₃)₄, toluene/ethanol, reflux; d) acetic acid, 35 °C; e) LiOH, THF, 90 °C.

Scheme 6

Synthesis of sulfoximine 19 as a mixture of epimers: a) chloramine‐T trihydrate, RT; b) H₂O₂, ethanol, CH₃CN, RT; c) sulfuric acid, methanol, RT; d) conc. sulfuric acid, CHCl₃, 0 °C.