RESUMEN
The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.
RESUMEN
The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.
Asunto(s)
Diseño de Fármacos , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Niacinamida/química , Inhibidores de Proteínas Quinasas/química , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Janus Quinasa 3/química , Janus Quinasa 3/metabolismo , Conformación Molecular , Simulación de Dinámica Molecular , Niacinamida/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Lisofosfolípidos/agonistas , Esfingosina/análogos & derivados , Relación Estructura-Actividad , Administración Oral , Animales , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Recuento de Linfocitos , Masculino , Ratas Endogámicas Lew , Receptores de Lisoesfingolípidos/agonistas , Esfingosina/agonistasRESUMEN
The synthesis and functionalization of amines are fundamentally important in a vast range of chemical contexts. We present an amine synthesis that repurposes two simple feedstock building blocks: olefins and nitro(hetero)arenes. Using readily available reactants in an operationally simple procedure, the protocol smoothly yields secondary amines in a formal olefin hydroamination. Because of the presumed radical nature of the process, hindered amines can easily be accessed in a highly chemoselective transformation. A screen of more than 100 substrate combinations showcases tolerance of numerous unprotected functional groups such as alcohols, amines, and even boronic acids. This process is orthogonal to other aryl amine syntheses, such as the Buchwald-Hartwig, Ullmann, and classical amine-carbonyl reductive aminations, as it tolerates aryl halides and carbonyl compounds.
RESUMEN
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, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Quinasa I-kappa B/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Tiazoles/química , Animales , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Femenino , Quinasa I-kappa B/metabolismo , Ratones , Ratones Endogámicos BALB C , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
A convenient, one-pot method for the construction of a variety of azaindoles using simple ketones and haloaminopyridines is described.
Asunto(s)
Compuestos Aza/síntesis química , Indoles/síntesis química , Cetonas/química , Paladio/química , Catálisis , Espectroscopía de Resonancia Magnética , Espectrometría de MasasRESUMEN
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
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
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.
Asunto(s)
Amidas/farmacología , Antiinflamatorios/farmacología , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Artritis Experimental/terapia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Masculino , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
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 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
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.