Identification of neutral 4-O-alkyl quinolone nonpeptide GnRH receptor antagonists.

A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists.

Syntheses and structure-activity relationship studies of piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists.

Syntheses and structure-activity relationships of piperidine-substituted quinolones as nonpeptide gonadotropin releasing hormone antagonists are described. Some of substituents on the piperidine ring that were investigated included a fused phenyl group, a (6R)-trifluoromethyl group, (6S) and (6R)-methyl group. This study showed that GnRH binding potency was tolerated by a small group at the 6-position of the piperidine, and blocking the 6-position by a trifluoromethyl group reduced clearance rate and increased oral bioavailability.

Modification of the pyridine moiety of non-peptidyl indole GnRH receptor antagonists.

The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs.

2-Arylindoles as gonadotropin releasing hormone (GnRH) antagonists: optimization of the tryptamine side chain.

A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents.