RESUMEN
Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.
Asunto(s)
Isoxazoles/síntesis química , Isoxazoles/farmacología , Lisofosfolípidos/agonistas , Esfingosina/análogos & derivados , Animales , Artritis Experimental/tratamiento farmacológico , Células CHO , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cricetinae , Cricetulus , Descubrimiento de Drogas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Sistema Linfático/citología , Sistema Linfático/efectos de los fármacos , Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Endogámicas Lew , Esfingosina/agonistas , Relación Estructura-Actividad , Timo/citología , Timo/efectos de los fármacosRESUMEN
The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease.
Asunto(s)
Acetamidas/química , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos con 3 Anillos/química , Quinasa I-kappa B/antagonistas & inhibidores , Acetamidas/síntesis química , Acetamidas/farmacología , Administración Oral , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed.
Asunto(s)
Proteína Quinasa 14 Activada por Mitógenos/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/farmacología , Animales , Cristalografía por Rayos X , Ratones , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Unión Proteica , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
A new series of tricyclic-based inhibitors of IKK have been derived from an earlier lead compound. The synthesis and structure-activity relationships (SAR) are described. Compound 4k inhibited TNF production in rats stimulated with LPS.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Imidazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Pirimidinas/síntesis química , Animales , Quinasa I-kappa B/metabolismo , Imidazoles/química , Imidazoles/farmacología , Lipopolisacáridos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The design and synthesis of a novel series of oxazole-, thiazole-, and imidazole-based inhibitors of IkappaB kinase (IKK) are reported. Biological activity was improved compared to the pyrazolopurine lead, and the expedient synthesis of the new tricyclic systems allowed for efficient exploration of structure-activity relationships. This, combined with an iterative rat cassette dosing strategy, was used to identify compounds with improved pharmacokinetic (PK) profiles to advance for in vivo evaluation.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/síntesis química , Quinasa I-kappa B/antagonistas & inhibidores , Imidazoles/síntesis química , Oxazoles/síntesis química , Tiazoles/síntesis química , Animales , Cristalografía por Rayos X , Femenino , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Quinasa I-kappa B/genética , Imidazoles/farmacocinética , Imidazoles/farmacología , Técnicas In Vitro , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Oxazoles/farmacocinética , Oxazoles/farmacología , Ratas , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The synthesis and structure-activity relationships (SAR) of p38 alpha MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38 alpha MAP kinase with excellent cellular potency toward the inhibition of TNFalpha production. Compound 2x was highly efficacious in vivo in inhibiting TNFalpha production in an acute murine model of TNFalpha production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38 alpha is also disclosed.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/químicaRESUMEN
2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Pirimidinas/síntesis química , Tiazoles/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Dasatinib , Femenino , Humanos , Técnicas In Vitro , Inflamación/sangre , Inflamación/inducido químicamente , Interleucina-2/antagonistas & inhibidores , Lipopolisacáridos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Moleculares , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity, and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 3 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo and was previously reported to reduce lung inflammation in a mouse model of ovalbumin induced allergy/asthma.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Sulfuros/síntesis química , Sulfuros/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Asma/patología , Células Cultivadas , Humanos , Hipersensibilidad/patología , Células Jurkat/efectos de los fármacos , Ratones , Neumonía/patología , Relación Estructura-ActividadRESUMEN
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 2 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Tiazoles/farmacología , Animales , Anticuerpos Monoclonales/efectos de los fármacos , Anticuerpos Monoclonales/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Interleucina-2/biosíntesis , Células Jurkat , Ratones , Estructura Molecular , Receptores de Antígenos de Linfocitos T/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
Nonreceptor protein tyrosine kinases including Lck, ZAP-70, and Itk play essential roles in T-cell receptor (TCR) signaling. Gene knockout studies have revealed that mice lacking these individual kinases exhibit various degrees of immunodeficiency; however, highly selective small molecule inhibitors of these kinases as potential immunosuppressive agents have not been identified. Here we discovered two novel compounds, BMS-488516 and BMS-509744, that potently and selectively inhibit Itk kinase activity. The compounds reduce TCR-induced functions including PLCgamma1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in vitro in both human and mouse cells. The inhibitors suppress the production of IL-2 induced by anti-TCR antibody administered to mice. BMS-509744 also significantly diminishes lung inflammation in a mouse model of ovalbumin-induced allergy/asthma. Our findings represent the first description of selective inhibitors to probe human Itk function and its associated pathway, and support the hypothesis that Itk is a therapeutic target for immunosuppressive and inflammatory diseases.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores Enzimáticos/farmacología , Pulmón/enzimología , Pulmón/patología , Activación de Linfocitos/efectos de los fármacos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Linfocitos T/enzimología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Línea Celular Tumoral , Inhibidores Enzimáticos/administración & dosificación , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Interleucina-2/antagonistas & inhibidores , Interleucina-2/biosíntesis , Células Jurkat , Pulmón/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Receptores de Antígenos de Linfocitos T/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/fisiología , Hipersensibilidad Respiratoria/enzimología , Hipersensibilidad Respiratoria/patología , Hipersensibilidad Respiratoria/prevención & control , Linfocitos T/metabolismoRESUMEN
A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.
Asunto(s)
Antiinflamatorios/química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Quinoxalinas/química , Quinoxalinas/farmacocinética , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Disponibilidad Biológica , Citocinas/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Enlace de Hidrógeno , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Pirazinas/química , Pirazinas/farmacología , Quinoxalinas/farmacología , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , Secuencia de Aminoácidos , Sitios de Unión , Diseño de Fármacos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) was prepared to elucidate their structure-activity relationships (SAR), selectivity and cell activity in the T-cell proliferation assay. BMS-350751 (2) and BMS-358233 (3) are identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.
Asunto(s)
Anilidas/síntesis química , Anilidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , División Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Conformación Proteica , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/enzimologíaRESUMEN
A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in the T-cell proliferation assay. BMS-243117 (compound 2) is identified as a potent, and selective Lck inhibitor with good cellular activity (IC(50)=1.1 microM) against T-cell proliferation.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , Adenosina Trifosfato/metabolismo , Sitios de Unión/efectos de los fármacos , División Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad , Especificidad por Sustrato , Linfocitos T/efectos de los fármacos , Urea/químicaRESUMEN
A series of anilino(imidazoquinoxaline) analogues bearing solubilizing side chains at the 6- and 7-positions of the fused phenyl ring has been prepared and evaluated for inhibition against Lck enzyme and of T-cell proliferation. Significant improvement of the cellular activity was achieved over the initial lead, compound 2.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , División Celular/efectos de los fármacos , Humanos , Indicadores y Reactivos , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacosRESUMEN
A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.