Synthesis and structure-activity relationships of 1-arylmethyl-5-aryl-6-methyluracils as potent gonadotropin-releasing hormone receptor antagonists

Based on the SAR from bicyclic gonadotropin-releasing hormone (GnRH) antagonists such as 6-aminomethyl-7-aryl-pyrrolo[1,2-alpha]pyrimid-4-ones (5) and 2-aryl-3-aminomethyl-imidazolo[1,2-alpha]pyrimid-5-ones (6a,b), a series of novel uracil compounds (8) were derived as GnRH antagonists. The synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed herein. Introduction of a small methyl substituent at the beta-position of the N3 side-chain improved the GnRH binding potency by 5-10-fold. Introduction of a methyl group of (R)-configuration at the alpha-carbon of the N-3 side-chain gave a modest improvement in binding affinity over the unsubstituted ethylene analogues. This modification enabled us to make uracil compounds without the labile 2-pyridylethyl motif on the basic nitrogen while still maintained excellent potency against the hGnRH receptor.