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The synthesis of a series of ( R )-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5 is described. SAR around C-5 of the uracil led to the discovery that a 2-thienyl or (2-phenyl)thiazol-4-yl group is required for optimal receptor binding. The best compound from the series had a binding affinity of 2 nM ( K i ) for the human GnRH receptor. A novel and convenient preparation of N -1-(2,6-difluorobenzyl)-6-methyluracil is also described.

A new class of small molecule GnRH antagonists, the 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils, was designed and a novel stereoselective synthesis for these compounds was developed. The stereochemical integrities of key intermediates (S)-6 and (R)-6 were confirmed by a combination of X-ray crystallography and chiral HPLC determinations. SAR studies were performed, which allowed the identification of derivatives (R)-9f, (R)-9h and (R)-12 as potent hGnRH antagonists (Ki=20 nM).

SAR studies of 2-arylimidazolo[1,2- a ]pyrimid-5-ones 10a – m , which were derived from initial lead 3a , resulted in the discovery of a series of potent nonpeptide human GnRH receptor antagonists. Compounds with good potency (e.g., 10e , K i =7.5 nM) were prepared by introduction of a 2-(2-pyridyl)ethyl at the basic nitrogen and a 3-pentyl ester at the 6-position of the bicyclic core.

In the process of developing GnRH receptor antagonists, a novel base-catalyzed cyclization of compounds 5a–b was discovered, which led to the formation of the 2-aryl pyrrolo[1,2-a]pyrimid-7-one core stuctures 6a–b. These intermediates were further modified at positions 1, 2, 4 and 6 to afford a series of potent GnRH antagonists with low nanomolar Ki values.

4-Benzylquinolines 5 , based on a series of isoquinolines 1 , were prepared and tested as inhibitors of the IGF/IGFBP-3 complex based on their ability to displace IGF-I from its binding to IGF-binding protein-3. SAR studies on the 6,7-dihydroxy moiety of the quinoline 5a showed that the catecol moiety could be replaced with other functional groups. Computational modeling of the 5a /mini-IGFBP-5 complex revealed the possible binding site of 5a on IGFBP-5.

A series of 1-benzoyl isoquinolines, based on compound 1, was synthesized and evaluated for their ability to displace IGF-I from its complex with IGF_binding protein-3. Successful modifications of 1 included the replacement of the 3,4-dihydroxybenzoyl group with a substituted benzyl group. These alternations culminated in the discovery of compounds such as 7o which had excellent in vitro potency (Ki=9.4 nM) but with one less of the labile catechol functionality of 1.

A new class of small molecule GnRH antagonists, the 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones, was designed and a novel synthesis for these compounds was developed. The synthesis utilizes a base-catalyzed intramolecular cyclization of fluoromethyl pyrimidone 5 to generate the bicyclic core. Amongst the compounds synthesized, we discovered some highly potent GnRH receptor antagonists (e.g., 12, K(i)=9 nM), which showed enhanced stability towards acidic physiological conditions compared to the des-fluoro analogues.

SAR studies of lead GnRH receptor antagonists 2a and 2b reported earlier resulted in the discovery of compound 10b which showed much higher potency ( K i =4.6 nM, compared with 2b , K i =230 nM) in which the 7-position of the imidazolo[1,2- a ]pyrimidone core was substituted with a methyl group, and the ester at the 6-position was replaced by the 3-methoxyphenyl group.

Initial SAR studies on 1-aminomethyl-2-aryl-3-cyano-pyrrolo[1,2- a ]pyrimid-7-one-6-carboxylates as human GnRH receptor antagonists were discussed. 2-(2-Methylaminoethyl)pyridine was discovered to be a key feature for generating active compounds. The best compound from the series had 25 nM ( K i ) binding affinity to human GnRH receptor.