Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats
| Autor: | Christie Lance Christopher, Mary A. Castro, Margaret L. Gregory, Rosemary Castillo, David Robert Luthin, Kenna Anderes, Ved P. Pathak, Qiang Ye, John M. May, Vazir Haresh N, Karen D. Nared-Hood, Paderes Genevieve Deguzman, Mark B. Anderson, Eugenia Kraynov |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
endocrine system medicine.medical_specialty DNA Complementary Tetrahydronaphthalenes Cell Survival Inositol Phosphates Gonadotropin-releasing hormone Pharmacology Biology In Vitro Techniques Gonadotropin-Releasing Hormone Mice Radioligand Assay Internal medicine medicine Animals Humans Anilides Testosterone Inositol phosphate Receptor Cells Cultured Chromatography High Pressure Liquid chemistry.chemical_classification Cell Membrane Antagonist Blood Proteins Luteinizing Hormone Rats Molecular Weight Endocrinology chemistry Competitive antagonist Molecular Medicine Luteinizing hormone Orchiectomy hormones hormone substitutes and hormone antagonists Receptors LHRH Hormone Protein Binding |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 305(2) |
| ISSN: | 0022-3565 |
| Popis: | 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 GnRH-stimulated 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 gonad-intact 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), des-Gly(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. |
| Databáze: | OpenAIRE |
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