RESUMO
In a recent methodological study investigating the synthesis of N-alkoxyazomethine ylides, an unexpected aminal byproduct was generated during our attempt to isolate O-benzyl-N-((trimethylsilyl)methyl)hydroxylamine. After a strategic investigation, silica gel was discovered to be the cause of the byproduct formation. Through the mechanistic insight from control and trapping experiments, we propose the formation of a methaniminium ion via a novel aza-Peterson reaction, which ultimately triggers a sequential iminium ion cascade sequence. Herein, we discuss the elucidation of this cascade reaction mechanism and the constraints for the byproduct formation.
RESUMO
Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.
Assuntos
Artrite Experimental/tratamento farmacológico , Desenho de Fármacos , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Artrite Experimental/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Janus Quinase 1/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , TYK2 Quinase/metabolismoRESUMO
A 71-year-old man underwent transcatheter edge-to-edge repair for treatment of severe functional mitral regurgitation.
Assuntos
Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Mitral , Masculino , Humanos , Idoso , Insuficiência da Valva Mitral/cirurgia , Valva Mitral/cirurgia , Cateterismo Cardíaco , Resultado do TratamentoRESUMO
Alternative access transcatheter aortic valve replacement (TAVR) consists primarily of 4 different options: transcaval, transaxillary, transcarotid, and transapical. While many centers have a preferred alternative access site, few papers have compared the outcomes of TAVR with each alternative access site. In this review, we examine the outcomes of TAVR at each alternative access site, focusing on mortality, stroke, bleeding, pacemaker insertion, paravalvular leakage, and discharge to home. Notable findings include higher mortality in the transapical group and higher stroke rate in the transaxillary group. On the basis of these data, we suggest that transcarotid TAVR might represent the second choice of approach for TAVR when alternate access is required.
Assuntos
Estenose da Valva Aórtica , Acidente Vascular Cerebral , Substituição da Valva Aórtica Transcateter , Humanos , Substituição da Valva Aórtica Transcateter/métodos , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Fatores de Risco , Resultado do Tratamento , Acidente Vascular Cerebral/epidemiologiaRESUMO
Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound 14 demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.
RESUMO
The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme. The study provides insight into the binding requirements for the design of potent hH-PGDS inhibitors.
Assuntos
Antialérgicos/química , Anti-Inflamatórios/química , Inibidores Enzimáticos/química , Oxirredutases Intramoleculares/antagonistas & inibidores , Lipocalinas/antagonistas & inibidores , Água/química , Antialérgicos/síntese química , Anti-Inflamatórios/síntese química , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Humanos , Oxirredutases Intramoleculares/metabolismo , Isoquinolinas/química , Lipocalinas/metabolismo , Naftalenos/química , Estrutura Terciária de ProteínaRESUMO
This report describes the design and synthesis of a series of CCR2 antagonists incorporating novel non-aryl/heteroaryl RHS (right hand side) motifs. Previous SAR in the area has suggested an aryl/heteroaryl substituent as a necessary structural feature for binding to the CCR2 receptor. Herein we describe the SAR with regards to potency (binding to hCCR2), dofetilide activity and metabolic stability (in vitro HLM) for this series. The resulting outcome was the identification of compounds with excellent properties for the investigation of the role of CCR2 in disease.
Assuntos
Desenho de Fármacos , Receptores CCR2/antagonistas & inibidores , Sítios de Ligação , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
The inhibition of PKC-zeta has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-zeta). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH(2) derivative. The analog displays good selectivity over other PKC isoforms (alpha, betaII, gamma, delta, epsilon, mu, theta, eta and iota/lambda) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).
Assuntos
Benzimidazóis/síntese química , Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Imidazóis/síntese química , Proteína Quinase C/química , Proteína Quinase C/isolamento & purificação , Benzimidazóis/farmacologia , Cristalografia por Raios X , Ciclina A/química , Quinase 2 Dependente de Ciclina/metabolismo , Desenho de Fármacos , Humanos , Imidazóis/farmacologia , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Isoformas de ProteínasRESUMO
BACKGROUND AND AIM OF THE STUDY: Since the introduction of its theoretical basis, patient-prosthesis mismatch (PPM) following aortic valve replacement (AVR) has been the subject of much debate. The study aim was to compare, by a propensity score adjustment, the survival and quality of life in elderly patients with PPM, to those of a population without mismatch. The analysis was focused on elderly patients, as their high prevalence of calcific aortic stenosis may increase the probability to receive a small-sized aortic prosthesis, and consequently to experience postoperative PPM. METHODS: A total of 163 patients aged > or = 75 years who underwent AVR was analyzed. The median logistic euroSCORE was 7.1%. PPM was considered to be present if the anticipated indexed effective orifice area (IEOA) was < or = 0.85 cm2/m2. The median follow up period was 37.4 months. The patients' quality of life was evaluated using the Short Form 12 (SF-12) Health Survey test. RESULTS: PPM was present in 43% of the patients. In multivariable analysis, patients with PPM were more often female, more often operated on for aortic degenerative calcification, had a larger body surface area, and more often received a bioprosthesis than those without mismatch. The survival analysis did not highlight any significant difference between the two groups. According to a multivariable analysis, the SF-12 physical component score of PPM patients was significantly inferior to that in patients without mismatch (p = 0.001). CONCLUSION: The study results suggest that moderate PPM does not have a negative impact on mid-term mortality in elderly patients after AVR. However, PPM was associated with a reduced quality of life in this elderly population.
Assuntos
Estenose da Valva Aórtica/mortalidade , Estenose da Valva Aórtica/psicologia , Valva Aórtica/cirurgia , Próteses Valvulares Cardíacas , Qualidade de Vida/psicologia , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVE: The aim of the study was to compare the quality of life of elderly patients undergoing aortic valve replacement with that of a reference group. PATIENTS: A total of 163 patients aged 75 years who underwent aortic valve replacement were analyzed. Quality of life was evaluated by the Short Form Health Survey test 12 (SF-12). The median follow-up period was 37.4 months. Quality of life follow-up was complete at 95.6% of mid-term survivors. Quality of life data was compared with published data of a sample of the Spanish population (n.1312) of the same age and same sex. RESULTS: Overall 30-day mortality was 7.4%. The mean SF-12 physical component score and SF-12 mental component score of the study population were 44,69 and 49,88 for woman and 47,38 and 56,19 for men, respectively. Our sample population showed a post operative quality of live comparable with that of the general population. CONCLUSIONS: Elderly patients who are candidates to aortic valve replacement represent a high risk population. Nevertheless, the quality of life achieved post-operatively is comparable with that of the general population.
Assuntos
Valva Aórtica/cirurgia , Implante de Prótese de Valva Cardíaca , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Feminino , Implante de Prótese de Valva Cardíaca/normas , Humanos , Masculino , EspanhaRESUMO
PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level of selectivity toward JAK3 is achieved by the covalent interaction of PF-06651600 with a unique cysteine residue (Cys-909) in the catalytic domain of JAK3, which is replaced by a serine residue in the other JAK isoforms. Importantly, 10 other kinases in the kinome have a cysteine at the equivalent position of Cys-909 in JAK3. Five of those kinases belong to the TEC kinase family including BTK, BMX, ITK, RLK, and TEC and are also inhibited by PF-06651600. Preclinical data demonstrate that inhibition of the cytolytic function of CD8+ T cells and NK cells by PF-06651600 is driven by the inhibition of TEC kinases. On the basis of the underlying pathophysiology of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, alopecia areata, and vitiligo, the dual activity of PF-06651600 toward JAK3 and the TEC kinase family may provide a beneficial inhibitory profile for therapeutic intervention.
Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Lectinas Tipo C/antagonistas & inibidores , Lectinas Tipo C/imunologia , CamundongosRESUMO
Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.
RESUMO
A modular, two-pot assembly of 7-arylpyrazolo[1,5- a]pyrimidones from aryl/heteroaryl halides and aminopyrazoles in library format was developed. Sonogashira coupling of aryl bromides with triethyl orthopropiolate, followed by in situ orthoester hydrolysis, provides access to ß-aryl ynoates, which undergo regioselective cyclocondensation with aminopyrazoles. The ability to vary the C7 vector of 7-arylpyrazolo[1,5- a]pyrimidones in two steps using readily available (hetero)aryl halides significantly enhances synthetic access to this challenging vector.
Assuntos
Pirazóis/química , Pirimidinonas/química , Catálise , Complexos de Coordenação/química , Hidrólise , Oxirredução , Paládio/química , EstereoisomerismoRESUMO
Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.
Assuntos
Cianamida/química , Cianamida/farmacologia , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Cianamida/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Janus Quinase 3/química , Masculino , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Distribuição TecidualRESUMO
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals. We hypothesized that a dual JAK1/TYK2 inhibitor will provide additional efficacy, while managing risk by optimizing selectivity against JAK2 driven hematopoietic changes. Our program began with a conformationally constrained piperazinyl-pyrimidine Type 1 ATP site inhibitor, subsequent work led to the discovery of PF-06700841 (compound 23), which is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868).
Assuntos
Antituberculosos/farmacologia , Artrite Experimental/prevenção & controle , Janus Quinase 1/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , TYK2 Quinase/antagonistas & inibidores , Tuberculose/complicações , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/microbiologia , Feminino , Estrutura Molecular , Ratos , Ratos Endogâmicos Lew , Tuberculose/microbiologiaRESUMO
Patients undergoing cardiac valve replacement may receive mechanical or bioprosthetic valves. Mechanical valves require lifelong anticoagulation but are durable and the need for a second surgery is up to eightfold times less than with bioprosthetic valves. Bioprosthetic valves do not require lifelong anticoagulation and thus are associated with fewer bleeding complications but they are less durable and associated with higher morbidity and mortality rates, particularly in younger patients. Anticoagulation with mechanical valves is achieved using warfarin; use of direct-acting oral anticoagulants is not indicated. Concomitant low-dose aspirin is recommended for patients with mechanical valves and as sole thromboembolism prophylaxis for patients receiving aortic or mitral bioprosthetic valves. If a patient taking warfarin is to undergo a surgical procedure that requires interruption of anticoagulation, bridging therapy with heparin is indicated if the patient has a mechanical aortic valve and any risk of thromboembolism, an older-generation mechanical aortic valve, or a mechanical mitral valve. Warfarin is teratogenic; pregnant women should take heparin. Patients with mechanical or bioprosthetic valves should receive antibiotic prophylaxis before some dental and surgical procedures to prevent endocarditis. Thrombolytic therapy should be considered in patients who develop a thrombus on a valve that does not resolve with heparin.
Assuntos
Anticoagulantes/uso terapêutico , Endocardite/prevenção & controle , Doenças das Valvas Cardíacas/cirurgia , Próteses Valvulares Cardíacas/efeitos adversos , Tromboembolia/prevenção & controle , Varfarina/uso terapêutico , Antibioticoprofilaxia/métodos , Bioprótese , Feminino , Heparina/uso terapêutico , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Gravidez , Complicações Cardiovasculares na Gravidez/prevenção & controle , Desenho de PróteseRESUMO
OBJECTIVE: This prospective study aimed to characterize the changes in blood lactate concentration and blood oxygen saturation in patients during the immediate postoperative period of cardiac surgery with extracorporeal circulation. METHODS: Blood samples were collected from 35 patients in a rapid and random order from the arterial line and from the proximal and distal port of a pulmonary artery catheter. RESULTS: The results showed no statistically significant differences between the blood oxygen saturation in the right atrium (72% ± 0.11%) and the blood oxygen saturation in the pulmonary artery (71% ± 0.08%). The blood lactate concentration in the right atrium was 1.7mmol/L ± 0.5mmol/L, and the blood lactate concentration in the pulmonary artery was 1.6mmol/L ± 0.5mmol/L (p < 0.0005). CONCLUSION: The difference between the blood lactate concentration in the right atrium and the blood lactate concentration in the pulmonary artery might be a consequence of the low blood lactate concentration in the blood from the coronary sinus, as it constitutes an important substrate for the myocardium during this period. The lack of differences between the blood oxygen saturation in the right atrium and the percentage of blood oxygen saturation in the pulmonary artery suggests a lower oxygen extraction by the myocardium given a lower oxygen consumption.
OBJETIVO: Caracterizar as modificações na concentração sanguínea do lactato e da saturação de oxigênio em pacientes no pós-operatório imediato de cirurgia cardíaca com circulação extracorpórea. MÉTODOS: Foram coletadas amostras de sangue de 35 pacientes, de forma rápida e aleatória, do acesso arterial e das portas proximal e distal de um cateter pulmonar. RESULTADOS: Não foram verificadas diferenças estatisticamente significantes entre saturação de oxigênio no átrio direito (72% ± 0,11%) e na artéria pulmonar (71% ± 0,08%). A concentração sanguínea de lactato no átrio direito foi de 1,7mmol/L ± 0,5mmol/L, enquanto na artéria pulmonar esta concentração foi de 1,6mmol/L ± 0,5mmol/L (p < 0,0005). CONCLUSÃO: A diferença entre as concentrações sanguíneas de lactato no átrio direito e na artéria pulmonar pode ser consequência da baixa concentração de lactato no sangue do seio coronário, já que o lactato é um importante substrato para o miocárdio durante este período. A ausência de diferenças entre saturação sanguínea de oxigênio no átrio direito e na artéria pulmonar sugere extração de oxigênio mais baixa pelo miocárdio, em razão do menor consumo de oxigênio.
Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Circulação Extracorpórea/métodos , Ácido Láctico/sangue , Oxigênio/sangue , Idoso , Feminino , Átrios do Coração , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Período Pós-Operatório , Estudos Prospectivos , Artéria PulmonarRESUMO
Cyclic GMP-AMP synthase (cGAS) is activated by ds-DNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response; dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology. We report here the structure of cGAS with dinucleotides and small molecule inhibitors, and kinetic studies of the cGAS mechanism. Our structural work supports the understanding of how ds-DNA activates cGAS, suggesting a site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. Mechanistic studies of cGAS provide the first kinetic constants for 2',3'-cGAMP formation, and interestingly, describe a catalytic mechanism where 2',3'-cGAMP may be a minor product of cGAS compared with linear nucleotides.
Assuntos
Nucleotídeos Cíclicos/química , Nucleotídeos Cíclicos/metabolismo , Nucleotidiltransferases/química , Nucleotidiltransferases/metabolismo , Asparagina/química , Sítios de Ligação , DNA/química , DNA/metabolismo , Humanos , Imunidade Inata , Cinética , Modelos Moleculares , Nucleotidiltransferases/genética , Conformação Proteica em alfa-HéliceRESUMO
Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past 2 decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within our research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme presented a unique challenge in the design of covalent inhibitors with appropriate pharmacodynamics properties coupled with limited unwanted off-target reactivity. This effort resulted in the identification of 11 (PF-06651600), a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this JAK3-specific inhibitor 11 led to its evaluation in several human clinical studies.
Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirróis/química , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Desenho de Fármacos , Humanos , Janus Quinase 3/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Pirróis/administração & dosagem , Pirróis/farmacologiaRESUMO
Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound, and establish a high throughput assay for the identification of next generation cGAS inhibitors.