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1.
Br J Dermatol ; 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38366639

RESUMO

BACKGROUND: Xeligekimab is a fully human monoclonal antibody that selectively neutralizes IL-17A and had shown potential efficacy in preliminary trials. OBJECTIVE: To evaluate the efficacy and safety of Xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200 mg Xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by extending the treatment schedule to GR1501 every 4 weeks for further 40 weeks. Efficacy was assessed by evaluating the Physician's Global Assessment (PGA) 0/1 and Psoriasis Area and Severity Index (PASI) 75/90/100 improvement. The safety profile was also evaluated. RESULTS: At week 12, The PASI 75/90/100 were achieved in 90.7%/74.4%/30.2%% patients in GR1501 group compared with 8.6%/1.4%/0% patients in placebo group, respectively. The PGA 0/1 were achieved in 74.4% patients of GR1501 group and 3.6% patients in placebo group, respectively. The PASI 75 and PGA 0/1 maintained until week 52. No unexpected adverse events were observed. CONCLUSION: Xeligekimab showed high efficacy and is well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.

2.
J Coll Physicians Surg Pak ; 34(2): 141-145, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38342861

RESUMO

OBJECTIVE: To explore the anti-BP230/180 and anti-BP180 antibodies in patients with bullous pemphigoid (BP) combined with neurological diseases, and to analyse the relevant factors. STUDY DESIGN: Analytical study. Place and Duration of the Study: Neurology Department, Cangzhou People's Hospital, Cangzhou, from April 2019 to June 2022. METHODOLOGY: Eighty BP patients were chosen based on associated neurological diseases, they were split into single (n=42) and combined groups (n=38). Expression of anti-BP180/230 antibodies was compared between the two groups. Associations with neurological diseases were analysed and the factors affecting the expression of anti-BP180/230 antibodies were explored. RESULTS: Out of 80 patients, 61 were positive for anti-BP180 antibodies and 58 were positive for anti-BP230 antibodies. The proportion of patients with positive anti-BP230/180 antibodies in the single group was considerably lower than in the combined group (p<0.05). Presence of both nervous system diseases and BP was found to be associated with the presence of anti-BP230/180 antibodies (p<0.001). Univariate analysis showed statistically significant association with age (<70 years, total IgE (>100 IU/ml), and EOS count >0.5 x 109/L (p<0.05). Logistic analysis demonstrated that age, total IgE and EOS count were independent risk factors affecting the expression of anti-BP180 and anti-BP23 antibodies (p<0.05). CONCLUSION: Serum anti-BP230/180 antibodies expression is abnormally high in BP patients having nervous system diseases. Combined nervous system diseases, age, total IgE and EOS count are independent risk factors affecting expression of anti-BP180/230 antibodies. KEY WORDS: Anti-BP180 antibody, Anti-BP230 antibody, Bullous pemphigoid, Nervous system diseases.


Assuntos
Doenças do Sistema Nervoso , Penfigoide Bolhoso , Humanos , Idoso , Colágeno Tipo XVII , Colágenos não Fibrilares , Autoantígenos , Autoanticorpos , Ensaio de Imunoadsorção Enzimática , Imunoglobulina E
3.
J Org Chem ; 86(13): 8851-8861, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34126006

RESUMO

We describe a stereodefined synthesis of the newly identified non-natural phosphorothioate cyclic dinucleotide (CDN) STING agonist, BMT-390025. The new route avoids the low-yielding racemic approach using P(III)-based reagents, and the stereospecific assembly of the phosphorothioate linkages are forged via the recently invented P(V)-based platform of the so-called PSI (Ψ) reagent system. This P(V) approach allows for the complete control of chirality of the P-based linkages and enabled conclusive evidence of the absolute configuration. The new approach offers robust procedures for preparing the stereodefined CDN in eight steps starting from advanced nucelosides, with late-stage direct drop isolations and telescoped steps enabling an efficient scale-up that proceeded in an overall 15% yield to produce multigram amounts of the CDN.

4.
Bioorg Med Chem Lett ; 30(12): 127204, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334911

RESUMO

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.


Assuntos
Compostos de Benzil/farmacologia , Compostos Heterocíclicos/farmacologia , Receptores do Ácido Retinoico/agonistas , Animais , Compostos de Benzil/química , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-Atividade , Receptor gama de Ácido Retinoico
6.
J Med Chem ; 60(12): 5193-5208, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28541707

RESUMO

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.


Assuntos
Artrite Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-Atividade , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Cães , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Coelhos
7.
Bioorg Med Chem Lett ; 27(13): 2849-2853, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28209465

RESUMO

Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined.


Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 27(4): 855-861, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28108251

RESUMO

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.


Assuntos
Aminas/química , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Doenças Autoimunes/tratamento farmacológico , Sítios de Ligação , Classe I de Fosfatidilinositol 3-Quinases , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Triazinas/química
9.
Bioorg Med Chem Lett ; 26(17): 4256-60, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27476421

RESUMO

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.


Assuntos
Aminas/química , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Triazinas/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Artrite/tratamento farmacológico , Artrite/metabolismo , Artrite/patologia , Sítios de Ligação , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
10.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 30(7): 706-9, 2010 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-20929126

RESUMO

OBJECTIVE: To reveal the possible role of combined therapy with Chinese drug and narrow broad ultraviolet B (NB-UVB) on keratinocytes apoptosis in skin lesion of psoriasis vulgaris (PV). METHODS: Skin samples were taken from 20 healthy subjects and 30 PV patients before and after they received the combined therapy for 8 weeks. SP immunohistochemical method was used to detect the expressions of Bcl-2, Caspase-3 and survivin in the samples. RESULTS: As compared with those in the normal skin, expression of Bcl-2 in PV skin was significantly lower (7.50 +/- 2.01 vs. 12.65 +/- 2.83), while expression of Caspase-3 (21.73 +/- 3.70 vs. 8.55 +/- 2.16), and survivin (23.90 +/- 2.82 vs. 7.06 +/- 1.96) were higher (all P < 0.01). After treatment, in skin of PV, Bcl-2 expression increased to 13.63 +/- 2.14, Caspase-3 and survivin decreased to 11.70 +/- 2.44 and 12.46 +/- 1.80, respectively (all P < 0.01), showing a normalizing trend. Moreover, patients' psoriasis area and severity index (PASI) score decreased from 14.24 +/- 3.42 before treatment to 3.52 +/- 1.07 after treatment (P < 0.01). CONCLUSION: The curing effect of the combined therapy with Chinese drug and NB-UVB in treating PV is possibly realized by way of regulating Bcl-2, Caspase-3 and survivin expressions to adjust keratinocyte apoptosis.


Assuntos
Fitoterapia , Psoríase/terapia , Pele/metabolismo , Terapia Ultravioleta , Adulto , Estudos de Casos e Controles , Caspase 3/metabolismo , Terapia Combinada , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Psoríase/metabolismo , Survivina , Adulto Jovem
12.
Bioorg Med Chem Lett ; 19(5): 1399-402, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19181527

RESUMO

A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Purinonas/síntese química , Animais , Humanos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Purinonas/metabolismo , Purinonas/farmacologia , Ratos , Receptor A2A de Adenosina/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 19(1): 119-22, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19014884

RESUMO

The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM.


Assuntos
Antagonistas de Receptor B1 da Bradicinina , Éteres/síntese química , Sulfonamidas/síntese química , Animais , Linhagem Celular , Técnicas de Química Combinatória , Humanos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Sulfonamidas/farmacologia
14.
Bioorg Med Chem Lett ; 18(20): 5420-3, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18815029

RESUMO

The discovery and synthesis of a series of (dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists from a small-molecule combinatorial library using a high-throughput calcium mobilization functional assay (HEK293-human OX2-R cell line) is described. Active compounds show a good correlation between high-throughput single concentration screening data and measured IC(50)s. Specific examples exhibit IC(50) values of approximately 20 nM using human orexin A as the peptide agonist for the orexin-2 receptor.


Assuntos
Acetamidas/síntese química , Química Farmacêutica/métodos , Peptídeos e Proteínas de Sinalização Intracelular/química , Neuropeptídeos/química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Acetamidas/química , Cálcio/química , Linhagem Celular , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Mutação , Receptores de Orexina , Orexinas , Temperatura
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