Combined experimental and quantum mechanical elucidation of the synthetically accessible stereoisomers of Hydroxyestradi
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Combined experimental and quantum mechanical elucidation of the synthetically accessible stereoisomers of Hydroxyestradienone (HED), the starting material for vilaprisan synthesis Tobias A. Plöger1 · Stefan Koep2 · Hans‑Christian Militzer3 · Andreas H. Göller4 Received: 15 July 2020 / Accepted: 10 October 2020 © Springer Nature Switzerland AG 2020
Abstract Selective progesterone receptor modulators are promising therapeutic options for the treatment of uterine fibroids. Vilaprisan, a new chemical entity that was discovered at Bayer is currently in clinical development. In this study we provide a combined experimental and quantum chemical approach providing the data that allowed to present hydroxyestradienone as an acceptable starting material for drug substance synthesis. Hydroxyestradienone has four stereogenic centers leading to 8 diastereomers and 16 enantiomers of which only six diastereomers were synthetically accessible but two not. A computational multistep protocol resulting in density functional P2PLYP-D3(BJ)/dev2-TZVPP Gibbs free energies and SMD solvation free energies led to a clear separation between the existing and the synthetically not accessible enantiomers, whereas multiple geometrybased and cheminformatic descriptors were not able to explain experimental findings. Keywords Synthetic accessibility · Quantum mechanics · Stereoisomerism · Cheminformatics
Introduction Uterine fibroids (myomas or leiomyomas), are benign tumors of the uterine smooth muscle and are the most common benign tumors in women. Between 50 and 60% of women are affected and between 15 and 30% of the cases are seriously symptomatic [1, 2]. The clinical symptoms of uterine fibroids are heavy menstrual bleeding, pelvic masses causing pressure and pain, obstetric complications, and even infertility [3, 4]. The therapeutic options for myomas range from surgical and nonsurgical interventional treatments to medical treatments [5]. Hysterectomy is the only treatment that definitely * Andreas H. Göller [email protected] 1
Product Supply, Pharmaceuticals, Bayer AG, 59192 Bergkamen, Germany
2
Product Supply, Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany
3
Chemical Development, Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany
4
Computational Molecular Design, Digital Technologies, Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany
solves the uterine fibroids and recurrence risk, [6] but is seen as the last option for women when other options have failed, for women that have satisfied their reproductive desire, and who accept the risk associated. Hormonal therapies reduce bleeding due to myomas, but there is contrasting data on the efficacy on fibroid size [7]. Gonadotropin-releasing hormone agonists (GnRHa) are the oldest class of drugs in this field. They induce a state of chemical castration, but also induce adverse effects, especially the reduction in bone density [8]. Since onset and progression of uterine fibroids are progesterone-dependent [9, 10], targeting the progesterone receptor (PR) is prom
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