RESUMO
Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).
Assuntos
Indenos/síntese química , Morfolinas/síntese química , Pirimidinas/síntese química , Receptores LHRH/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Técnicas In Vitro , Indenos/química , Indenos/farmacologia , Fosfatos de Inositol/biossíntese , Masculino , Morfolinas/química , Morfolinas/farmacologia , Orquiectomia , Hipófise/metabolismo , Pirimidinas/química , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testosterona/antagonistas & inibidores , Testosterona/metabolismoRESUMO
A novel series of non-peptide derivatives 1, 14, and 15 that bind with high affinity to the human GnRH receptors is discussed. The discovery was made from screening our in-house libraries that contained the active structure 2 along with a trace amount of a second active structure 1 that was derived from an acid-induced rearrangement. From this structure type 1, a series of guanidine and non-guanidine containing analogues were prepared and tested as GnRH receptor antagonists. Compounds derived from this series bind to both human and rat GnRH receptors and antagonize GnRH-mediated increases in inositol phosphate production in cells containing recombinant human receptors. These compounds or their analogues may be useful as therapeutic agents for the treatment of hormone-dependent pathologies including prostate, breast and ovarian cancers.
Assuntos
Guanidina/análogos & derivados , Receptores LHRH/antagonistas & inibidores , Animais , Desenho de Fármacos , Guanidina/farmacologia , Antagonistas de Hormônios/química , Antagonistas de Hormônios/farmacologia , Humanos , Monoéster Fosfórico Hidrolases/biossíntese , Ligação Proteica , Ratos , Receptores LHRH/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of derivatives of mono- and diaminopyrimidines 1 potently displaced binding of a radiolabeled GnRH analogue to human and rat GnRH receptors. Analogues from these series competitively antagonized GnRH-stimulated increases in extracellular acidification in vitro and suppressed GnRH-mediated increases in circulating luteinizing hormone (LH) in castrated rats and testosterone in intact rats. These compounds or their analogues may be useful in treating sex hormone-dependent disease.
Assuntos
Pirimidinas/farmacologia , Receptores LHRH/antagonistas & inibidores , Animais , Castração , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Hormônio Luteinizante/sangue , Hormônio Luteinizante/efeitos dos fármacos , Masculino , Pirimidinas/síntese química , Pirimidinas/química , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Testosterona/sangueRESUMO
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.