RESUMEN
Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC(50)=0.07 µM, %F=18), are reported.
Asunto(s)
Activación Enzimática/efectos de los fármacos , Hepacivirus/enzimología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Indoles/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Diseño de Fármacos , Compuestos Heterocíclicos/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.
Asunto(s)
Antitrombina III , Piperidinas/química , Piridonas/química , Inhibidores de Serina Proteinasa , Trombosis/tratamiento farmacológico , ortoaminobenzoatos/química , Administración Oral , Animales , Antitrombina III/administración & dosificación , Antitrombina III/síntesis química , Antitrombina III/farmacocinética , Derivación Arteriovenosa Quirúrgica , Sitios de Unión , Disponibilidad Biológica , Modelos Animales , Conejos , Inhibidores de Serina Proteinasa/administración & dosificación , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-Actividad , Trombosis/etiologíaRESUMEN
Using a high-throughput screening strategy, a series of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-ones was identified that inhibit the cyclin-dependent kinase (CDK) 4/cyclin D1 complex-mediated phosphorylation of a protein substrate with IC(50)s in the low micromolar range. On the basis of preliminary structure-activity relationships (SAR), a model was proposed in which these inhibitors occupy the ATP-binding site of the enzyme, forming critical hydrogen bonds to the same residue (Val96) to which the amino group in ATP is presumed to bind. X-ray diffraction studies on a later derivative bound to CDK2 support this binding mode. Iterative cycles of synthesis and screening lead to a novel series of potent, CDK2-selective 6-(arylmethyl)pyrazolopyrimidinones. Placement of a hydrogen-bond donor in the meta-position on the 6-arylmethyl group resulted in approximately 100-fold increases in CDK4 affinity, giving ligands that were equipotent inhibitors of CDK4 and CDK2. These compounds exhibit antiproliferative effects in the NCI HCT116 and other cell lines. The potency of these antiproliferative effects is enhanced in anilide derivatives and translates into tumor growth inhibition in a mouse xenograft model.
Asunto(s)
Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Células Cultivadas , Cristalografía por Rayos X , Ciclina D1/antagonistas & inhibidores , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Fosforilación , Proteínas Proto-Oncogénicas/metabolismo , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel and potent compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls. Substitutions at the para position of the phenyl ring at C3 were generally well-tolerated; however, larger groups were generally inactive. For alkyls directly attached to C3, longer chain substituents were not tolerated; however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j, was examined in detail and was determined to have a biological profile consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q, complexed with CDK2 was determined and showed the inhibitor residing in the adenosine 5'-triphosphate pocket of the enzyme.
Asunto(s)
Quinasas CDC2-CDC28 , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Proteínas Proto-Oncogénicas , Pirazoles/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , División Celular/efectos de los fármacos , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina , Quinasa 4 Dependiente de la Ciclina , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Modelos Moleculares , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.
Asunto(s)
Antivirales/farmacología , Benzazepinas/farmacología , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica , Animales , Antivirales/química , Antivirales/farmacocinética , Benzazepinas/química , Benzazepinas/farmacocinética , Perros , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Indoles/química , Indoles/farmacocinética , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Ratas , Relación Estructura-ActividadRESUMEN
BACKGROUND: Since the cannabinoid receptor 1 (CB1) antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. DISCUSSION: In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity. RESULTS: The structure-activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC(50) values of approximately 1 nM for the rat CB1 receptor binding. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.
Asunto(s)
Fármacos Antiobesidad/química , Obesidad/tratamiento farmacológico , Oxadiazoles/química , Pirazoles/química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Tiadiazoles/química , Administración Oral , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/uso terapéutico , Sitios de Unión , Disponibilidad Biológica , Simulación por Computador , Humanos , Ratones , Oxadiazoles/farmacocinética , Oxadiazoles/uso terapéutico , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Ratas , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-Actividad , Tiadiazoles/farmacocinética , Tiadiazoles/uso terapéuticoRESUMEN
Factor VIII (fVIII) is a serum protein in the coagulation cascade that nucleates the assembly of a membrane-bound protease complex on the surface of activated platelets at the site of a vascular injury. Hemophilia A is caused by a variety of mutations in the factor VIII gene and typically requires replacement therapy with purified protein. We have determined the structure of a fully active, recombinant form of factor VIII (r-fVIII), which consists of a heterodimer of peptides, respectively containing the A1-A2 and A3-C1-C2 domains. The structure permits unambiguous modeling of the relative orientations of the 5 domains of r-fVIII. Comparison of the structures of fVIII, fV, and ceruloplasmin indicates that the location of bound metal ions and of glycosylation, both of which are critical for domain stabilization and association, overlap at some positions but have diverged at others.
Asunto(s)
Factor VIII/química , Factor VIII/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Dimerización , Factor VIII/genética , Glicosilación , Modelos Moleculares , Unión Proteica , Estructura Cuaternaria de Proteína , Estructura Terciaria de ProteínaRESUMEN
Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.
Asunto(s)
Obesidad/tratamiento farmacológico , Oxadiazoles/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Simulación por Computador , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties.
Asunto(s)
Diaminas/química , Diaminas/farmacología , Inhibidores del Factor Xa , Anticoagulantes/química , Anticoagulantes/farmacología , Sitios de Unión , Humanos , Modelos Moleculares , Estructura Molecular , Tiempo de Protrombina , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
Cyclin-dependent kinases (CDKs) play a key role in regulating the cell cycle. The cyclins, their activating agents, and endogenous CDK inhibitors are frequently mutated in human cancers, making CDKs interesting targets for cancer chemotherapy. Our aim is the discovery of selective CDK4/cyclin D1 inhibitors. An ATP-competitive pyrazolopyrimidinone CDK inhibitor was identified by HTS and docked into a CDK4 homology model. The resulting binding model was consistent with available SAR and was validated by a subsequent CDK2/inhibitor crystal structure. An iterative cycle of chemistry and modeling led to a 70-fold improvement in potency. Small substituent changes resulted in large CDK4/CDK2 selectivity changes. The modeling revealed that selectivity is largely due to hydrogen-bonded interactions with only two kinase residues. This demonstrates that small differences between enzymes can efficiently be exploited in the design of selective inhibitors.
Asunto(s)
Quinasas CDC2-CDC28/antagonistas & inhibidores , Ciclina A/antagonistas & inhibidores , Ciclina D1/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pirimidinonas/farmacología , Secuencia de Aminoácidos , Quinasas CDC2-CDC28/química , Quinasa 2 Dependiente de la Ciclina , Quinasa 4 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/química , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas/química , Pirimidinonas/química , Homología de Secuencia de Aminoácido , Especificidad por SustratoRESUMEN
New indeno[1,2-c]pyrazol-4-one cyclin dependent kinase inhibitors have been disclosed. The most promising compounds are nanomolar enzyme inhibitors with excellent activity against tumor cells. The most advanced compound retains cell culture activity even in the presence of human serum proteins. The most advanced compound did not kill the normal fibroblast line AG1523.