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 antago nist (+/-) are reported. Chiral amino alcohols were prepared from the appro priate cyclic D- or L-amino acids by the Arndt-Eistert homologation followe d by reduction of the resulting esters. Incorporation of these pharmacophor es was achieved via a novel Mitsunobu alkylation of 4-hydroxyquinolones. Th e key amine pharmacophore for binding to the rat GnRH receptor was most act ive in the S-configuration. Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency. (C) 1999 Else vier Science Ltd. Ail rights reserved.