Background: Elagolix, the first orally active gonadotropin-releasing hormone (GnRH or LHRH) antagonist, approved by FDA in 2018 for the treatment of endometriosis [1], is a uracil-based derivative having a stereocenter with the (R)-configuration and a second source of chirality, called atropisomerism. The methyl group at the 6-position of uracil and the fluorine at the ortho position of the 5-aryl group causes a slow rotation around the C-C bond between the two aromatic rings. Previous studies on two analogues of elagolix [2] evidenced a stereo-preference for receptor interaction toward one of the isolated atropisomers and showed that the elimination of atropisomerism decreased the activity. Aims: Since the increase in the steric hindrance or the modulation of electronic factors, which can affect the atropisomeric propensity, have not been evaluated yet, the aim of this project is the design, synthesis, characterization, and biological evaluation of new potential uracil-based GnRH antagonists to gain a deeper knowledge about the role of atropisomerism for this class of compounds. Methods: This project exploits a multidisciplinary approach starting from the synthesis of elagolix, followed by the design (by the aid of molecular modelling techniques) and the synthesis of new derivatives as single thermally stable atropisomers. The compounds will be fully characterized by their physico-chemical properties (NMR, MS, XRD) and biological activity (in vitro binding to the pituitary and peripheral GnRH receptors) after the separation of the two isomers, achieved by traditional methods or by biotransformation. Results: The synthesis of elagolix was accomplished implementing some modifications with respect to a literature procedure. The NMR and HPLC analyses performed on this molecule confirmed that, in solution, elagolix exists as an interchangeable mixture of atropisomers. The design, through molecular modelling techniques, and the synthesis of some new derivatives will be presented. Conclusion: This project aims at disclosing new potential orally available GnRH antagonists. The synthesis, separation, characterization, and biological evaluation of the obtained mixtures of atropisomers will provide information to clarify the interaction mechanism of this class of analogues with their target. References: 1. Lamb, Y. N. Elagolix: First Global Approval. Drugs 2018, 78 (14), 1501-1508. 2. Zhao, L.; Guo, Z. Q.; Chen, Y. S.; Hu, T.; Wu, D. P.; Zhu, Y. F.; Rowbottom, M.; Gross, T. D.; Tucci, F. C.; Struthers, R. S.; Xie, Q.; Chen, C. 5-Aryluracils as potent GnRH antagonists—Characterization of atropisomers. Bioorg. Med. Chem. Lett. 2008, 18 (11), 3344-3349.

Design, synthesis, characterization, and biological activity of new derivatives of elagolix, a potent GnRH antagonist / S. Ciceri, D.R. Colombo, P. Ferraboschi, P. Grisenti, S.V. Sforna, F. Meneghetti. ((Intervento presentato al 40. convegno European School of Medicinal Chemistry-ESMEC tenutosi a online nel 2021.

Design, synthesis, characterization, and biological activity of new derivatives of elagolix, a potent GnRH antagonist

S. Ciceri;D.R. Colombo;P. Ferraboschi;F. Meneghetti
2021-06-29

Abstract

Background: Elagolix, the first orally active gonadotropin-releasing hormone (GnRH or LHRH) antagonist, approved by FDA in 2018 for the treatment of endometriosis [1], is a uracil-based derivative having a stereocenter with the (R)-configuration and a second source of chirality, called atropisomerism. The methyl group at the 6-position of uracil and the fluorine at the ortho position of the 5-aryl group causes a slow rotation around the C-C bond between the two aromatic rings. Previous studies on two analogues of elagolix [2] evidenced a stereo-preference for receptor interaction toward one of the isolated atropisomers and showed that the elimination of atropisomerism decreased the activity. Aims: Since the increase in the steric hindrance or the modulation of electronic factors, which can affect the atropisomeric propensity, have not been evaluated yet, the aim of this project is the design, synthesis, characterization, and biological evaluation of new potential uracil-based GnRH antagonists to gain a deeper knowledge about the role of atropisomerism for this class of compounds. Methods: This project exploits a multidisciplinary approach starting from the synthesis of elagolix, followed by the design (by the aid of molecular modelling techniques) and the synthesis of new derivatives as single thermally stable atropisomers. The compounds will be fully characterized by their physico-chemical properties (NMR, MS, XRD) and biological activity (in vitro binding to the pituitary and peripheral GnRH receptors) after the separation of the two isomers, achieved by traditional methods or by biotransformation. Results: The synthesis of elagolix was accomplished implementing some modifications with respect to a literature procedure. The NMR and HPLC analyses performed on this molecule confirmed that, in solution, elagolix exists as an interchangeable mixture of atropisomers. The design, through molecular modelling techniques, and the synthesis of some new derivatives will be presented. Conclusion: This project aims at disclosing new potential orally available GnRH antagonists. The synthesis, separation, characterization, and biological evaluation of the obtained mixtures of atropisomers will provide information to clarify the interaction mechanism of this class of analogues with their target. References: 1. Lamb, Y. N. Elagolix: First Global Approval. Drugs 2018, 78 (14), 1501-1508. 2. Zhao, L.; Guo, Z. Q.; Chen, Y. S.; Hu, T.; Wu, D. P.; Zhu, Y. F.; Rowbottom, M.; Gross, T. D.; Tucci, F. C.; Struthers, R. S.; Xie, Q.; Chen, C. 5-Aryluracils as potent GnRH antagonists—Characterization of atropisomers. Bioorg. Med. Chem. Lett. 2008, 18 (11), 3344-3349.
GnRH; elagolix; stereoselectivity; atropisomerism; endometriosis; uterine fibroids
Settore BIO/10 - Biochimica
Settore CHIM/08 - Chimica Farmaceutica
Settore CHIM/06 - Chimica Organica
Società Chimica Italiana. Divisione di Chimica Farmaceutica
https://eventi.uniurb.it/esmec/
Design, synthesis, characterization, and biological activity of new derivatives of elagolix, a potent GnRH antagonist / S. Ciceri, D.R. Colombo, P. Ferraboschi, P. Grisenti, S.V. Sforna, F. Meneghetti. ((Intervento presentato al 40. convegno European School of Medicinal Chemistry-ESMEC tenutosi a online nel 2021.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/853808
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