Learn More
The 2-aryltryptamine class of GnRH receptor antagonists has been modified to incorporate carboxamide and acetamide substituents at the indole 5-position. With either a phenol or methanesulfonamide terminus on the N-aralkyl side chain, potent binding affinity to the GnRH receptor was achieved. A functional assay for GnRH antagonism was even more sensitive to(More)
A pyridine side-chain terminus has been incorporated into the indole-5-carboxamide and indole-5-acetamide series of GnRH antagonists. Potent activity was observed in binding and functional assays. Certain branched or cyclic tertiary amides were identified as preferred in each series. Alkylation of the side-chain secondary amine had generally unfavorable(More)
The dog GnRH receptor was cloned to facilitate the identification and characterization of selective nonpeptide GnRH antagonists. The dog receptor is 92% identical to the human GnRH receptor. Despite such high conservation, the quinolone-based nonpeptide GnRH antagonists were clearly differentiated by each receptor species. By contrast, peptide antagonist(More)
A nonpeptidyl GnRH receptor antagonist (1), with a unique 2-arylindole core, was identified through the Merck in-house screening for binding affinity on the rat GnRH receptor. SAR studies directed toward the alkoxy-ethanolamine and 2-aryl groups resulted in a simpler lead structure with improved activity. This compound 50 exhibits a 60-fold improvement in(More)
Individual experimental animals used in our studies on bovine leukemia virus (BLV) are routinely screened for the presence of antibodies to the three bovine lymphotropic retroviruses. We utilized these screening methods to examine frozen sera from eight herds for antibodies to BLV, bovine visna virus (BVV) and bovine syncytial virus (BSV). Serum samples(More)
Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the(More)
SAR studies which focused upon the C-6 position of a recently described series of quinolone gonadotropin releasing hormone antagonists are reported. Synthetic access to diverse quinolone-6-carboxamides was achieved via the palladium-catalyzed amino-carbonylation reactions of iodide 4 with various amines. Amides related to 9y were especially potent,(More)
Screening of the Merck sample collection for non-peptide compounds with binding affinity for the rat GnRH receptor led to the identification of the substituted quinolone (1) as a lead compound in the search for a non-peptide GnRH receptor antagonist. Substantial improvements in potency (approximately 300 fold) were achieved by addition of an alkyl amine at(More)
The discovery of the potency-enhancing effect of 5-substitutions on the novel 2-arylindoles as nonpeptidyl GnRH receptor antagonists led to the identification of several analogues with high affinities on the GnRH receptor. The syntheses and SARs of these 5-substituted-2-arylindole analogues are reported.