RESUMO
A novel series of pyrrolopyrazole-based protein kinase C ß II inhibitors has been identified from high-throughput screening. Herein, we report our initial structure-activity relationship studies with a focus on optimizing compound ligand efficiency and physicochemical properties, which has led to potent inhibitors with good cell permeability.
Assuntos
Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirazóis/química , Ensaios de Triagem em Larga Escala , Proteína Quinase C/metabolismo , Proteína Quinase C beta , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
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.