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Gonadotropin-releasing hormone (GnRH) receptor antagonists have potential in treating numerous hormone-dependent pathologies including cancers of the prostate, breast, and ovary, endometriosis, and fertility disorders. An unmet clinical need exists for an orally available GnRH receptor antagonist. Guided by structure-activity relationships, ligand-based targeted library designs, and biomarker measurements, our discovery efforts have yielded a novel, small molecule GnRH receptor antagonist, 5- [(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide (CMPD1). CMPD1 bound with low nanomolar affinities to human, rat, and mouse GnRH receptors (6.0, 3.8, and 2.2 nM, respectively). CMPD1 was more than 100-fold selective for GnRH receptors versus various G-protein-coupled receptors and other enzymes and ion channels. In cells expressing recombinant rat GnRH receptors, CMPD1 was a competitive antagonist of GnRHstimulated increases in extracellular acidification rates in Cytosensor microphysiometer assays. In cells expressing recombinant human GnRH receptors, CMPD1 was a potent inhibitor of GnRH-stimulated total inositol phosphate accumulation. The effects of CMPD1 on circulating levels of luteinizing hormone (LH) and testosterone were studied in castrated and intact male rats, respectively. Intravenous and oral administration of CMPD1 dose dependently suppressed GnRH-mediated elevations of LH in castrated male rats and testosterone in gonadintact male rats. Moreover, CMPD1, when given at 20 mg/kg i.v. to intact male rats, inhibited the elevations of LH and testosterone stimulated by the superagonist of GnRH, [D-Ala 6 , desGly 10 ]GnRH (GnRH-A). These data suggest that CMPD1 is a potent, selective, orally active GnRH receptor antagonist that may have potential application as a therapeutic agent for treating hormone-dependent cancers and diseases.Gonadotropin-releasing hormone (GnRH) is a neuroendocrine decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-ProGly-NH 2 ) synthesized in the neurovascular terminals of the hypothalamus and is secreted in a pulsatile manner directly into the hypophyseal portal blood supply. GnRH selectively binds specific receptors on the membranes of the anterior pituitary gonadotroph cells to stimulate synthesis and release of the gonadotropic hormones [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)]. LH and FSH stimulate gonadal production of sex steroids and gametogenesis, respectively. GnRH, as the primary regulator of LH, is consequently the primary regulator of the sex hormones testosterone and estrogen. GnRH and its analogs have stimulated much interest because of their potential therapeutic benefit in treating sex hormone-dependent diseases such as prostate, ovarian, and breast cancer, as well as endometriosis, uterine fibroids, benign prostate hyperplasia, fertility disorders, and precocious puberty (Huirne and Lambalk, 2001). In contrast to GnRH agonists, which are associated with an initial surge in LH and testosterone ...

A new one-pot nitration employing tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in dichloromethane to provide a ready source of the nitronium triflate nitrating agent is presented. Rapid and selective nitration with a variety of aromatic and heteroaromatic substrates is achieved resulting in the synthesis of several novel organic compounds. A distinct advantage is the removal of undesired byproducts by aqueous workup. This very mild nitration permits large-scale syntheses and gives high isolated product yields that often require no further purification. This tetramethylammonium nitrate-based nitration also has been applied to microwave-assisted conditions, and the results with several compounds are outlined.

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