RESUMEN
To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Estilbenos/química , Estilbenos/farmacología , Secuencia de Aminoácidos , Animales , Línea Celular , Humanos , Conformación Molecular , Datos de Secuencia Molecular , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Quinolinas/química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Sitios de Unión , Glucemia/metabolismo , Cristalografía por Rayos X , Diabetes Mellitus Experimental/metabolismo , Perros , Transferencia Resonante de Energía de Fluorescencia , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Ligandos , Ratones , Conformación Molecular , Estructura Terciaria de Proteína , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Aumento de Peso/efectos de los fármacosRESUMEN
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiofenos/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Humanos , Isoxazoles/farmacología , Naftalenos/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Tiofenos/farmacocinéticaRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Asunto(s)
Isoxazoles/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Animales , Cristalografía por Rayos X , Transferencia Resonante de Energía de Fluorescencia , Isoxazoles/química , Isoxazoles/farmacología , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibition of acetyl-CoA carboxylase (ACC) may prevent lipid-induced insulin resistance and type 2 diabetes, making the enzyme an attractive pharmaceutical target. Although the enzyme is highly conserved amongst animals, only the yeast enzyme structure is available for rational drug design. The use of biophysical assays has permitted the identification of a specific C-terminal truncation of the 826-residue human ACC2 carboxyl transferase (CT) domain that is both functionally competent to bind inhibitors and crystallizes in their presence. This C-terminal truncation led to the determination of the human ACC2 CT domain-CP-640186 complex crystal structure, which revealed distinctions from the yeast-enzyme complex. The human ACC2 CT-domain C-terminus is comprised of three intertwined alpha-helices that extend outwards from the enzyme on the opposite side to the ligand-binding site. Differences in the observed inhibitor conformation between the yeast and human structures are caused by differing residues in the binding pocket.
Asunto(s)
Acetil-CoA Carboxilasa/química , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/aislamiento & purificación , Acetil-CoA Carboxilasa/metabolismo , Acetiltransferasas/antagonistas & inhibidores , Secuencia de Aminoácidos , Sitios de Unión , Dicroismo Circular , Cristalografía por Rayos X , Ácidos Grasos/metabolismo , Polarización de Fluorescencia , Humanos , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica , Desnaturalización Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ERalpha and ERbeta binding affinity ranging from micromolar to low nanomolar.
Asunto(s)
Naftalenos/síntesis química , Naftalenos/farmacología , Receptores de Estrógenos/agonistas , Técnicas Químicas Combinatorias , Moduladores de los Receptores de Estrógeno/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Ligandos , Estructura Molecular , Naftalenos/química , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Relación Estructura-ActividadRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Colestasis/tratamiento farmacológico , Proteínas de Unión al ADN/agonistas , Isoxazoles/síntesis química , Isoxazoles/farmacología , Naftalenos/síntesis química , Naftalenos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Administración Oral , Animales , Ácidos Carboxílicos/química , Colestasis/metabolismo , Colestasis/patología , Cristalografía por Rayos X , Proteínas de Unión al ADN/química , Modelos Animales de Enfermedad , Perros , Mucosa Gástrica/metabolismo , Haplorrinos , Isoxazoles/química , Ratones , Conformación Molecular , Estructura Molecular , Naftalenos/química , Ratas , Receptores Citoplasmáticos y Nucleares/química , Estómago/efectos de los fármacos , Relación Estructura-Actividad , Factores de Transcripción/químicaRESUMEN
We report the synthesis and in vitro activity of a series of novel pyrrolidinyl pyridones and pyrazinones as potent inhibitors of prolyl oligopeptidase (POP). Within this series, compound 39 was co-crystallized within the catalytic site of a human chimeric POP protein which provided a more detailed understanding of how these inhibitors interacted with the key residues within the catalytic pocket.
Asunto(s)
Piridonas/síntesis química , Piridonas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Serina Endopeptidasas/efectos de los fármacos , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Conformación Molecular , Estructura Molecular , Prolil Oligopeptidasas , Piridonas/sangre , Piridonas/química , Pirrolidinas/sangre , Pirrolidinas/química , Inhibidores de Serina Proteinasa/sangre , Inhibidores de Serina Proteinasa/químicaRESUMEN
Explorations of the S(1') subsite of ACE2 via modifications of the P(1') methylene biphenyl moiety of thiol-based metalloprotease inhibitors led to improvements in ACE2 selectivity versus ACE and NEP, while maintaining potent ACE2 inhibition.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Peptidil-Dipeptidasa A/metabolismo , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacología , Enzima Convertidora de Angiotensina 2 , Sitios de Unión , Humanos , Modelos Moleculares , Estructura Molecular , Proteínas Recombinantes , Relación Estructura-ActividadRESUMEN
Screening of a metalloprotease library led to the identification of a thiol-based dual ACE/NEP inhibitor as a potent ACE2 inhibitor. Modifications of the P(1) benzyl moiety led to improvements in ACE2 potency as well as to increased selectivity versus ACE and NEP.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/química , Peptidil-Dipeptidasa A/efectos de los fármacos , Compuestos de Sulfhidrilo/química , Enzima Convertidora de Angiotensina 2 , Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Peptidil-Dipeptidasa A/genética , Relación Estructura-Actividad , Especificidad por Sustrato , Compuestos de Sulfhidrilo/metabolismo , Compuestos de Sulfhidrilo/farmacologíaRESUMEN
The estrogen-related receptor alpha (ERRalpha) is a potential target for activation in the treatment of metabolic disease. To date, no small-molecule agonists of ERRalpha have been identified despite several high-throughput screening campaigns. We describe the synthesis and profiling of a small array of compounds designed on the basis of a previously reported agonist-bound crystal structure of the closely related receptor ERRgamma. The results suggest that ERRalpha may be intractable as a direct target for pharmacologic activation.
Asunto(s)
Hidrazonas/química , Hidrazonas/farmacología , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/química , Sitios de Unión , Cristalografía por Rayos X , Agonismo Inverso de Drogas , Transferencia Resonante de Energía de Fluorescencia , Células HeLa , Humanos , Hidrazonas/síntesis química , Receptores de Estrógenos/antagonistas & inhibidores , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Cetonas/química , Cetonas/farmacocinética , Administración Oral , Disponibilidad Biológica , Catepsina K , Catepsinas/química , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/administración & dosificación , Humanos , Cetonas/administración & dosificación , Conformación Proteica , Relación Estructura-ActividadRESUMEN
X-ray crystal structures of the ligand binding domain (LBD) of the estrogen-related receptor-gamma (ERRgamma) were determined that describe this receptor in three distinct states: unliganded, inverse agonist bound, and agonist bound. Two structures were solved for the unliganded state, the ERRgamma LBD alone, and in complex with a coregulator peptide representing a portion of receptor interacting protein 140 (RIP140). No significant differences were seen between these structures that both exhibited the conformation of ERRgamma seen in studies with other coactivators. Two structures were obtained describing the inverse agonist-bound state, the ERRgamma LBD with 4-hydroxytamoxifen (4-OHT), and the ERRgamma LBD with 4-OHT and a peptide representing a portion of the silencing mediator of retinoid and thyroid hormone action protein (SMRT). The 4-OHT structure was similar to other reported inverse agonist bound structures, showing reorientation of phenylalanine 435 and a displacement of the AF-2 helix relative to the unliganded structures with little other rearrangement occurring. No significant changes to the LBD appear to be induced by peptide binding with the addition of the SMRT peptide to the ERRgamma plus 4-OHT complex. The observed agonist-bound state contains the ERRgamma LBD, a ligand (GSK4716), and the RIP140 peptide and reveals an unexpected rearrangement of the phenol-binding residues. Thermal stability studies show that agonist binding leads to global stabilization of the ligand binding domain. In contrast to the conventional mechanism of nuclear receptor ligand activation, activation of ERRgamma by GSK4716 does not appear to involve a major rearrangement or significant stabilization of the C-terminal helix.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/química , Receptores de Estrógenos/química , Sitios de Unión , Dicroismo Circular , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Ligandos , Modelos Moleculares , Complejos Multiproteicos , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Estrógenos/agonistas , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Electricidad EstáticaRESUMEN
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
Asunto(s)
Amidas , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa , Cetonas , Pirrolidinas , Amidas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Sitios de Unión , Catepsina K , Catepsinas/química , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Humanos , Concentración 50 Inhibidora , Cetonas/síntesis química , Cetonas/farmacocinética , Cetonas/farmacología , Modelos Moleculares , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Inhibidores de Serina Proteinasa , Relación Estructura-ActividadRESUMEN
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Asunto(s)
Aldehídos/química , Catepsinas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Semicarbazonas/farmacología , Animales , Catepsina K , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Modelos Moleculares , Conformación Molecular , Profármacos/síntesis química , Profármacos/química , Profármacos/farmacología , Ratas , Semicarbazonas/síntesis química , Semicarbazonas/química , Solubilidad , Relación Estructura-ActividadRESUMEN
The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRgamma LBD confirms the molecular basis of the selectivity.
Asunto(s)
Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Receptores de Estrógenos/efectos de los fármacos , Tamoxifeno , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Receptor alfa de Estrógeno/efectos de los fármacos , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tamoxifeno/análogos & derivados , Tamoxifeno/síntesis química , Tamoxifeno/farmacologíaRESUMEN
Ketoheterocyclic inhibitors of cathepsin K have been disclosed. SAR of potency enhancing P2-P3 groups coupled with ketoheterocyclic warheads to provide cathepsin K inhibitors have been described. In addition, a novel route to access alpha-ketothiazoles using a key thioamide functionality has been disclosed. The mild method employed allows for the presence of diverse functional groups, such as amide and carbamate functionalities, commonly found in protease inhibitors that have peptidomimetic scaffolds. This new method should provide a quick entry into functionally diverse protease inhibitors.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Compuestos Heterocíclicos/síntesis química , Sitios de Unión , Catepsina B/antagonistas & inhibidores , Catepsina K , Catepsina L , Cisteína Endopeptidasas , Compuestos Heterocíclicos/farmacología , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Unión Proteica , Proteínas Recombinantes , Relación Estructura-ActividadRESUMEN
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
Asunto(s)
Amidas/síntesis química , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Cetonas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Catepsina K , Catepsinas/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Modelos Animales de Enfermedad , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/metabolismo , Cetonas/farmacocinética , Cetonas/farmacología , Ratas , Ratas Wistar , Solubilidad , Relación Estructura-ActividadRESUMEN
Conversion of the proline-derived cyanamide lead to an acyclic cyanamide capable of forming an additional hydrogen bond with cathepsin K resulted in a large increase in inhibitory activity. An X-ray structure of a co-crystal of a cyanamide with cathepsin K confirmed the enzyme interaction. Furthermore, a representative acyclic cyanamide inhibitor 6r was able to attenuate bone resorption in the rat calvarial model.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Cianamida/química , Inhibidores de Cisteína Proteinasa/farmacología , Osteogénesis/efectos de los fármacos , Animales , Sitios de Unión , Resorción Ósea , Catepsina B/antagonistas & inhibidores , Catepsina H , Catepsina K , Catepsina L , Cristalografía por Rayos X , Cisteína Endopeptidasas , Inhibidores de Cisteína Proteinasa/síntesis química , Modelos Animales de Enfermedad , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Unión Proteica , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The first small molecule agonists of the estrogen-related receptors have been identified. GSK4716 (3) and GSK9089 (4) show binding to ERRgamma with remarkable selectivity over the classical estrogen receptors. Notably, in cell-based reporter assays, 3 mimics the protein ligand PGC-1alpha in activation of human ERRbeta and ERRgamma.