RESUMEN
The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.
Asunto(s)
Bencimidazoles/farmacología , Ácidos Carboxílicos/farmacología , Inhibidores Enzimáticos/farmacología , Isomerasa de Peptidilprolil/antagonistas & inhibidores , Fosfatos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Dominio Catalítico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA , Isomerasa de Peptidilprolil/metabolismo , Relación Estructura-ActividadRESUMEN
Multiproperty lead optimization that satisfies multiple biological endpoints remains a challenge in the pursuit of viable drug candidates. Optimization of a given lead compound to one having a desired set of molecular attributes often involves a lengthy iterative process that utilizes existing information, tests hypotheses, and incorporates new data. Within the context of a data-rich corporate setting, computational tools and predictive models have provided the chemists a means for facilitating and streamlining this iterative design process. This chapter discloses an actual library design scenario for following up a lead compound that inhibits 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme. The application of computational tools and predictive models in the targeted library design of adamantyl amide 11ß-HSD1 inhibitors is described. Specifically, the multiproperty profiling using our proprietary PGVL (Pfizer Global Virtual Library) Hub is discussed in conjunction with the structure-based component of the library design using our in-house docking tool AGDOCK. The docking simulations were based on a piecewise linear potential energy function in combination with an efficient evolutionary programming search engine. The library production protocols and results are also presented.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/química , Adamantano/farmacología , Descubrimiento de Drogas/métodos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/síntesis química , Adamantano/metabolismo , Algoritmos , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Cobayas , Células HEK293 , Humanos , Ligandos , Ratones , Modelos Moleculares , Conformación Proteica , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/metabolismo , Relación Estructura-Actividad , Termodinámica , Interfaz Usuario-ComputadorRESUMEN
Highly selective PI3K inhibitors with subnanomolar PI3Kα potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communication, we describe the rationale behind the installation of a critical triazole moiety to maintain the intricate H-bonding network within the PI3K receptor leading to both better potency and selectivity. Furthermore, optimization of the C-4 phenyl group was exploited to maximize the compounds mTOR selectivity.
RESUMEN
The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Amidas/química , Inhibidores Enzimáticos/química , Hipoglucemiantes/química , Pirrolidinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/síntesis química , Adamantano/química , Adamantano/farmacología , Amidas/síntesis química , Amidas/farmacología , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cobayas , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Relación Estructura-ActividadRESUMEN
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).
Asunto(s)
Indenos/síntesis química , Morfolinas/síntesis química , Pirimidinas/síntesis química , Receptores LHRH/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Técnicas In Vitro , Indenos/química , Indenos/farmacología , Fosfatos de Inositol/biosíntesis , Masculino , Morfolinas/química , Morfolinas/farmacología , Orquiectomía , Hipófisis/metabolismo , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Testículo/efectos de los fármacos , Testículo/metabolismo , Testosterona/antagonistas & inhibidores , Testosterona/metabolismoRESUMEN
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.
Asunto(s)
Anilidas/farmacología , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Tetrahidronaftalenos/farmacología , Anilidas/metabolismo , Animales , Proteínas Sanguíneas/metabolismo , Membrana Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cromatografía Líquida de Alta Presión , ADN Complementario/biosíntesis , ADN Complementario/genética , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/análogos & derivados , Humanos , Técnicas In Vitro , Fosfatos de Inositol/metabolismo , Hormona Luteinizante/metabolismo , Masculino , Ratones , Peso Molecular , Orquiectomía , Unión Proteica , Ensayo de Unión Radioligante , Ratas , Receptores LHRH/metabolismo , Testosterona/sangre , Tetrahidronaftalenos/metabolismoRESUMEN
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.
Asunto(s)
Pirimidinas/farmacología , Receptores LHRH/antagonistas & inhibidores , Animales , Castración , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Hormona Luteinizante/sangre , Hormona Luteinizante/efectos de los fármacos , Masculino , Pirimidinas/síntesis química , Pirimidinas/química , Ensayo de Unión Radioligante , Ratas , Relación Estructura-Actividad , Testosterona/sangreRESUMEN
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.