RESUMO
Phosphoinositide 3-kinases generate lipid-based second messengers that control an array of intracellular signaling pathways. In particular, phosphoinositide 3-kinases delta (PI3Kδ) is expressed primarily in hematopoietic cells and plays an important role in B-cell development and function. B cells play a critical role in autoimmune diseases by producing autoantibodies. Studies have therefore increasingly focused on PI3Kδ as a therapeutic target for the treatment of inflammatory and autoimmune diseases. One such autoimmune disease is systemic lupus erythematosus (SLE). SLE is a chronic systemic autoimmune disease with repeated recurrence and remission, and autoantibodies play an important role in its pathogenesis. Here, we examined the pharmacological profile of the novel PI3Kδ selective inhibitor AS2819899 and investigated its therapeutic potential against SLE in a NZB/W F1 mouse lupus-like nephritis model, a widely-used SLE mouse model. AS2819899 prevented B and T cell activation in vitro, and inhibited antibody production in a T-cell independent de novo antibody production mouse model. In the spontaneous NZB/W F1 mouse model, AS2819899 treatment significantly reduced anti-dsDNA antibody titers and improved kidney dysfunction. Further, AS2819899 inhibited the memory recall reaction in a T-cell dependent antibody production mouse model, suggesting that AS2819899 can potentially maintain remission of SLE. Moreover, we identified a pharmacodynamics marker for AS2819899 that may be useful in clinical studies. These results indicate that AS2819899 may be an attractive therapeutic candidate for SLE, including the maintenance of remission.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Nefrite Lúpica/tratamento farmacológico , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Modelos Animais de Doenças , Feminino , Imunoglobulina M/imunologia , Nefrite Lúpica/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NZB , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Chemical optimization of the 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (THPP) scaffold was conducted with a focus on cellular potency while maintaining high selectivity against PI3K isoforms. Compound 11f was identified as a potent, highly selective and orally available PI3Kδ inhibitor. In addition, 11f exhibited efficacy in an in vivo antibody production model. The desirable drug-like properties and in vivo efficacy of 11f suggest its potential as a drug candidate for the treatment of autoimmune diseases and leukocyte malignancies.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Animais , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Humanos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Pirrolidinas/farmacocinéticaRESUMO
Chemical optimization of pyrazolopyridine 1, focused on cellular potency, isoform selectivity and microsomal stability, led to the discovery of the potent, selective and orally available PI3Kδ inhibitor 5d. On the basis of its desirable potency, selectivity and pharmacokinetic profiles, 5d was tested in the trinitrophenylated aminoethylcarboxymethyl-Ficoll (TNP-Ficoll)-induced antibody production model, and showed higher antibody inhibition than a 4-fold oral dose of the starting compound 1. These excellent results suggest that 5d is a potential candidate for further studies in the treatment of autoimmune diseases and leukocyte malignancies.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Biologia Computacional , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Phosphatidylinositol-3-kinase (PI3K)δ inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kδ inhibitors, compound 12a was identified as a potent PI3Kδ inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kδ inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure-activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kδ inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kδ over other PI3Ks with good oral exposure in mice.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Administração Oral , Animais , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Humanos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Nucleares/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/síntese química , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidoresRESUMO
The Janus kinase (JAK) family of tyrosine kinases is associated with various cytokine receptors. JAK1 and JAK3 play particularly important roles in the immune response, and their inhibition is expected to provide targeted immune modulation. Several oral JAK inhibitors have recently been developed for treating autoimmune diseases, including rheumatoid arthritis (RA). Here, we investigated the pharmacological effects of peficitinib (formerly known as ASP015K), a novel, chemically synthesized JAK inhibitor. We found that peficitinib inhibited JAK1 and JAK3 with 50% inhibitory concentrations of 3.9 and 0.7 nM, respectively. Peficitinib also inhibited IL-2-dependent T cell proliferation in vitro and STAT5 phosphorylation in vitro and ex vivo. Furthermore, peficitinib dose-dependently suppressed bone destruction and paw swelling in an adjuvant-induced arthritis model in rats via prophylactic or therapeutic oral dosing regimens. Peficitinib also showed efficacy in the model by continuous intraperitoneal infusion. Area under the concentration versus time curve (AUC) at 50% inhibition of paw swelling via intraperitoneal infusion was similar to exposure levels of AUC at 50% inhibition via oral administration, implying that AUC might be important for determining the therapeutic efficacy of peficitinib. These data suggest that peficitinib has therapeutic potential for the oral treatment of RA.
Assuntos
Adamantano/análogos & derivados , Artrite Experimental/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Niacinamida/análogos & derivados , Adamantano/administração & dosagem , Adamantano/farmacologia , Adamantano/uso terapêutico , Adjuvantes Imunológicos/efeitos adversos , Administração Oral , Animais , Artrite Experimental/induzido quimicamente , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Parenterais , Masculino , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Fosforilação/efeitos dos fármacos , Ratos , Fator de Transcrição STAT5/sangue , Fator de Transcrição STAT5/metabolismo , Linfócitos T/fisiologiaRESUMO
Nonsteroidal anti-inflammatory drugs (NSAIDs) are now understood to fall into one of two agent classes in clinical use. Traditional NSAIDs inhibit both cyclooxygenases-1 and 2 (COX-1, 2), which act as key enzymes catalyzing the same reaction in the production of prostaglandins (PGs), while the second class of NSAIDs selectively inhibit COX-2. Inhibition of the inducible COX-2 isoform is believed to be responsible for the therapeutic effects of NSAIDs, such as anti-inflammatory, analgesic, and antipyretic effects, while COX-1 inhibition results in side-effects on the gastrointestinal (GI) system. In the present study, however, we changed this notion that inhibiting only COX-1 causes adverse effects. We discovered FK881, a specific COX-1 inhibitor which exhibits a 650-fold ratio for human whole blood COX-1/COX-2 and rats in vivo. In rats, FK881 dose dependently inhibited carrageenan-induced paw edema (ED30: 22 mg/kg; diclofenac ED30: 3.6 mg/kg, rofecoxib ED30: 26 mg/kg) and paw swelling associated with adjuvant arthritis (ED50: 17 mg/kg; diclofenac ED50: 1.4 mg/kg, rofecoxib ED50: 1.8 mg/kg). Further, FK881 dose dependently inhibited acetic acid-induced writhing in mice (ED50: 19 mg/kg; diclofenac ED50: 14 mg/kg, rofecoxib ED50: >100mg/kg) and adjuvant arthritis hyperalgesia in rats (ED50: 1.8 mg/kg; diclofenac ED50: 1.0mg/kg, rofecoxib ED50: 0.8mg/kg). However, unlike traditional NSAIDs, GI tolerability was improved, although the antipyretic effect of FK881 was weak (NOEL: >320 mg/kg; diclofenac NOEL: <1mg/kg, rofecoxib NOEL: 100 mg/kg). These results suggest that FK881 may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis.
Assuntos
Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Triazóis/farmacologia , Ácido Acético , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/fisiopatologia , Células CHO , Carragenina , Cricetinae , Cricetulus , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/toxicidade , Inibidores de Ciclo-Oxigenase/toxicidade , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Técnicas In Vitro , Masculino , Camundongos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/fisiopatologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Úlcera Gástrica/induzido quimicamenteRESUMO
Bradykinin has been suggested to be involved in allergic diseases. In this study, we tested the effect of FK3657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl)-oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide), an orally active non-peptide bradykinin B(2) receptor antagonist, on allergic airway disease models in guinea pigs. FK3657 given orally inhibited bradykinin-induced or dextran sulfate (an activator of kinin-kallikrein cascade)-induced bronchoconstriction and plasma extravasation in the lower airways (trachea and main bronchi) and nasal mucosa of guinea pigs with ED(50) of 0.04-0.23 mg/kg. In the antigen-induced dual asthmatic response model of guinea pigs, FK3657 significantly attenuated the late phase asthmatic response, but not the immediate asthmatic response. FK3657 also significantly inhibited the 2,4-tolylene diisocyanate (TDI)-induced plasma extravasation in nasal mucosa of TDI-sensitized guinea pigs. These results suggest that oral FK3657 may be useful for asthma or allergic rhinitis as a therapeutic drug.