A new class of GnRH receptor modulators endowed with atropisomerism

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 an additional source of chirality, called atropisomerism, arising from the slow rotation about the C-C bond due to the interaction of the of the o-fluorine of the 5-aryl group with the methyl at the 6-position of the uracil moiety and the electronegative oxygen atom of the carbonyl at the 4-position. After the recognition and characterization of the atropisomers of elagolix through spectroscopic, analytical and theoretical techniques, the design and synthesis of some analogues differently substituted at the 6- or 4-position of the uracil moiety were carried out. The increase of the steric hindrance and/or the modulation of the electronic factors at these positions were able to affect the atropisomeric properties of the molecule. Indeed, some of the obtained compounds show an interconversion time between the atropisomers higher than elagolix, allowing their separation and analyses as single atropisomers. The planned biological tests will provide further insight into the role of atropisomerism in this class of compounds and unveil new potential orally available GnRH antagonists.