Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity

Stereospecific introduction of a methyl group to the indole-3-side chain en hanced activity in our tryptamine-derived series of GnRH receptor antagonis ts. Further improvements were achieved by variation of the bicyclic amino m oiety of the tertiary amide and by adjustment of the tether length to a pyr idine or pyridone terminus. These modifications culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys. (C) 2001 Elsevier Science Ltd. All right s reserved.