Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists

Synthesis and in vitro activity of the enantiomers of quinolone GnRH antagonist (±)-1 are reported. Chiral amino alcohols were prepared from the appropriate cyclic D- or L-amino acids by the Arndt-Eistert homologation followed by reduction of the resulting esters. Incorporation of these pharmacophores was achieved via a novel Mitsunobu alkylation of 4-hydroxyquinolones. The key amine pharmacophore for binding to the rat GnRH receptor was most active in the S-configuration. Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency.