title: Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats.
abstract: 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.
authors.affiliation: Research Pharmacology, Pfizer Global Research and Development-La Jolla/Agouron Pharmaceuticals, Inc., 10724 Science Center Drive, San Diego, CA 92121, USA. kenna.anderes@pfizer.com
authors.forename: Kenna L
authors.initials: KL
authors.lastname: Anderes
authors.forename: David R
authors.initials: DR
authors.lastname: Luthin
authors.forename: Rosemary
authors.initials: R
authors.lastname: Castillo
authors.forename: Eugenia A
authors.initials: EA
authors.lastname: Kraynov
authors.forename: Mary
authors.initials: M
authors.lastname: Castro
authors.forename: Karen
authors.initials: K
authors.lastname: Nared-Hood
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Gregory
authors.forename: Ved P
authors.initials: VP
authors.lastname: Pathak
authors.forename: Lance C
authors.initials: LC
authors.lastname: Christie
authors.forename: Genevieve
authors.initials: G
authors.lastname: Paderes
authors.forename: Haresh
authors.initials: H
authors.lastname: Vazir
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ye
authors.forename: Mark B
authors.initials: MB
authors.lastname: Anderson
authors.forename: John M
authors.initials: JM
authors.lastname: May
mesh_terms: D000813:Anilides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D008970:Molecular Weight; D009919:Orchiectomy; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D011966:Receptors, LHRH / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C474253:5-((3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl)-N-(2,4,6-trimethoxyphenyl)-2-furamide; D000813:Anilides; D001798:Blood Proteins; D018076:DNA, Complementary; D007295:Inositol Phosphates; D011966:Receptors, LHRH; D013764:Tetrahydronaphthalenes; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone