Elagolix is the first non-peptide orally active gonadotropin-releasing hormone (GnRH) antagonist approved for the treatment of sex-hormone dependent diseases such as endometriosis and uterine fibroids. Chemically it is an uracil-based derivative having a stereocenter with (R)-configuration and a second source of chirality, called atropisomerism, that arise from the interaction of the o-fluorine of the 5-aryl group with the methyl group at the 6-position of the uracil moiety and the electronegative oxygen atom of the carbonyl functionality, which causes a slow rotation about the C-C bond. Previous studies on two analogues of elagolix evidenced the importance of atropisomerism for this class of compounds showing a remarkable difference on the activity of the two isolated atropisomers. Since the increase in the steric hindrance or the modulation of electronic factors, which can affect the atropisomeric propensity of elagolix, have not been deeply evaluated yet, the aim of this research is the design, synthesis, characterization, and biological evaluation of new potential uracil-based GnRH antagonists to gain a deeper knowledge of the role of atropisomerism and to disclose new potential orally available GnRH antagonists. To reach this aim, the synthesis of elagolix was accomplished improving some steps of a literature procedure. Moreover, some elagolix analogues differently substituted at the 6- and/or 4-position of the uracil moiety were designed and synthetised with the support of molecular modelling techniques. Two of them present an interconversion time between the atropisomers higher than elagolix. The research work will proceed with the separation and analysis of the single atropisomers in order to understand if they are endowed with different biological properties.

Elagolix analogues as potential new GnRH antagonists / S. Ciceri, D. Colombo, E. Fassi, P. Ferraboschi, G. Grazioso, P. Grisenti, F. Meneghetti. ((Intervento presentato al 6. convegno BioMeTra Workshop tenutosi a Segrate nel 2022.

Elagolix analogues as potential new GnRH antagonists

S. Ciceri
Primo
;
D. Colombo
Secondo
;
E. Fassi;P. Ferraboschi;G. Grazioso;F. Meneghetti
Ultimo
2022

Abstract

Elagolix is the first non-peptide orally active gonadotropin-releasing hormone (GnRH) antagonist approved for the treatment of sex-hormone dependent diseases such as endometriosis and uterine fibroids. Chemically it is an uracil-based derivative having a stereocenter with (R)-configuration and a second source of chirality, called atropisomerism, that arise from the interaction of the o-fluorine of the 5-aryl group with the methyl group at the 6-position of the uracil moiety and the electronegative oxygen atom of the carbonyl functionality, which causes a slow rotation about the C-C bond. Previous studies on two analogues of elagolix evidenced the importance of atropisomerism for this class of compounds showing a remarkable difference on the activity of the two isolated atropisomers. Since the increase in the steric hindrance or the modulation of electronic factors, which can affect the atropisomeric propensity of elagolix, have not been deeply evaluated yet, the aim of this research is the design, synthesis, characterization, and biological evaluation of new potential uracil-based GnRH antagonists to gain a deeper knowledge of the role of atropisomerism and to disclose new potential orally available GnRH antagonists. To reach this aim, the synthesis of elagolix was accomplished improving some steps of a literature procedure. Moreover, some elagolix analogues differently substituted at the 6- and/or 4-position of the uracil moiety were designed and synthetised with the support of molecular modelling techniques. Two of them present an interconversion time between the atropisomers higher than elagolix. The research work will proceed with the separation and analysis of the single atropisomers in order to understand if they are endowed with different biological properties.
Elagolix; GnRH antagonist; Atropisomerism
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/10 - Biochimica
Settore CHIM/06 - Chimica Organica
https://www.biometra.unimi.it/ecm/home/aggiornamenti-e-archivi/tutte-le-notizie/content/workshop-biometra-2022.0000.UNIMIDIRE-99359
Elagolix analogues as potential new GnRH antagonists / S. Ciceri, D. Colombo, E. Fassi, P. Ferraboschi, G. Grazioso, P. Grisenti, F. Meneghetti. ((Intervento presentato al 6. convegno BioMeTra Workshop tenutosi a Segrate nel 2022.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/939377
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