RESUMO
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.
RESUMO
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.
Assuntos
Desenho de Fármacos , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Niacinamida/química , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Janus Quinase 3/química , Janus Quinase 3/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Niacinamida/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Artrite Experimental/tratamento farmacológico , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Relação Estrutura-Atividade , Administração Oral , Animais , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Contagem de Linfócitos , Masculino , Ratos Endogâmicos Lew , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/agonistasRESUMO
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.
RESUMO
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.
Assuntos
Acetamidas/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/química , Quinase I-kappa B/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/farmacologia , Administração Oral , Animais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Quinase I-kappa B/antagonistas & inibidores , Imidazóis/química , Inibidores de Proteínas Quinases/química , Piridinas/química , Tiazóis/química , Animais , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Quinase I-kappa B/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
A convenient, one-pot method for the construction of a variety of azaindoles using simple ketones and haloaminopyridines is described.
Assuntos
Compostos Aza/síntese química , Indóis/síntese química , Cetonas/química , Paládio/química , Catálise , Espectroscopia de Ressonância Magnética , Espectrometria de MassasRESUMO
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.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Imidazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Animais , Quinase I-kappa B/metabolismo , Imidazóis/química , Imidazóis/farmacologia , Lipopolissacarídeos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Quinase I-kappa B/antagonistas & inibidores , Imidazóis/síntese química , Oxazóis/síntese química , Tiazóis/síntese química , Animais , Cristalografia por Raios X , Feminino , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Quinase I-kappa B/genética , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Oxazóis/farmacocinética , Oxazóis/farmacologia , Ratos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Sulfetos/síntese química , Sulfetos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Asma/patologia , Células Cultivadas , Humanos , Hipersensibilidade/patologia , Células Jurkat/efeitos dos fármacos , Camundongos , Pneumonia/patologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Anticorpos Monoclonais/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Interleucina-2/biossíntese , Células Jurkat , Camundongos , Estrutura Molecular , Receptores de Antígenos de Linfócitos T/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
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.
Assuntos
Amidas/farmacologia , Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Tiazóis/farmacologia , Quinases da Família src/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Artrite Experimental/terapia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores Enzimáticos/farmacologia , Pulmão/enzimologia , Pulmão/patologia , Ativação Linfocitária/efeitos dos fármacos , Proteínas Tirosina Quinases/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Linhagem Celular Tumoral , Inibidores Enzimáticos/administração & dosagem , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Interleucina-2/antagonistas & inibidores , Interleucina-2/biossíntese , Células Jurkat , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/fisiologia , Hipersensibilidade Respiratória/enzimologia , Hipersensibilidade Respiratória/patologia , Hipersensibilidade Respiratória/prevenção & controle , Linfócitos T/metabolismoRESUMO
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.
Assuntos
Anti-Inflamatórios/química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Quinoxalinas/química , Quinoxalinas/farmacocinética , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Disponibilidade Biológica , Citocinas/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Ligação de Hidrogênio , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pirazinas/química , Pirazinas/farmacologia , Quinoxalinas/farmacologia , Quinases da Família src/antagonistas & inibidoresRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Tiazóis/síntese química , Tiazóis/farmacologia , Trifosfato de Adenosina/metabolismo , Sítios de Ligação/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Desenho de Fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade , Especificidade por Substrato , Linfócitos T/efeitos dos fármacos , Ureia/químicaRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Divisão Celular/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacosRESUMO
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.