RESUMO
BACKGROUND: Distal embolization during primary percutaneous coronary intervention (p-PCI) in the treatment of ST-segment elevation myocardial infarction (STEMI) is associated with a poor prognosis. In this situation, thrombectomy is performed to prevent distal embolization and to restore myocardial reperfusion. The aim of our study was to determine angiographic predictors of angiographically visible distal embolization (AVDE) in patients with STEMI treated by pPCI with thrombectomy. PATIENTS AND METHODS: This prospective study included all consecutive patients who underwent pPCI with thrombectomy for STEMI at our institution between October 2011 and December 2014 AVDE was defined as a distal filling defect with an abrupt cut-off in one of the peripheral coronary branches of the infarct-related artery, distal to the angioplasty site. Thrombectomy was considered positive when it removed thrombi, and successful when it improved coronary flow. RESULTS: Among the 346 patients included, 59 (17%) developed AVDE during pPCI. In multivariate analysis, the infarct-related right coronary artery (OR: 2.48, 95% CI: 1.36-4.52; pâ¯= 0.003) and a culprit lesion diameter of >3â¯mm (OR : 1.90, 95% CI: 1.01-3.56; pâ¯= 0.048) were identified as independent factors associated with AVDE during pPCI with thrombectomy for STEMI. The success of thrombectomy and the Syntax score were not associated with AVDE. CONCLUSION: AVDE complicating pPCI with thrombectomy in STEMI is frequent (17%) and a successful thrombectomy does not rule out AVDE.
Assuntos
Angioplastia Coronária com Balão , Angiografia Coronária , Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Trombectomia , Resultado do TratamentoRESUMO
This study describes the pharmacokinetic (PK) and pharmaco-dynamic (PD) profile of N-(5-(4-(5-(((2R,6S)-2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1H-indazol-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide (GSK2292767A), a novel low-solubility inhaled phosphoinositide 3-kinase delta (PI3Kδ) inhibitor developed as an alternative to 2-(6-(1H-indol-4-yl)-1H-indazol-4-yl)-5-((4-isopropylpiperazin-1-yl)methyl)oxazole (nemiralisib), which is a highly soluble inhaled inhibitor of PI3Kδ with a lung profile consistent with once-daily dosing. GSK2292767A has a similar in vitro cellular profile to nemiralisib and reduces eosinophilia in a murine PD model by 63% (n = 5, P < 0.05). To explore whether a low-soluble compound results in effective PI3Kδ inhibition in humans, a first time in human study was conducted with GSK2292767A in healthy volunteers who smoke. GSK2292767A was generally well tolerated, with headache being the most common reported adverse event. PD changes in induced sputum were measured in combination with drug concentrations in plasma from single (0.05-2 mg, n = 37), and 14-day repeat (2 mg, n = 12) doses of GSK2292767A. Trough bronchoalveolar lavage (BAL) for PK was taken after 14 days of repeat dosing. GSK2292767A displayed a linear increase in plasma exposure with dose, with marginal accumulation after 14 days. Induced sputum showed a 27% (90% confidence interval 15%, 37%) reduction in phosphatidylinositol-trisphosphate (the product of phosphoinositide 3-kinase activation) 3 hours after a single dose. Reduction was not maintained 24 hours after single or repeat dosing. BAL analysis confirmed the presence of GSK2292767A in lung at 24 hours, consistent with the preclinical lung retention profile. Despite good lung retention, target engagement was only present at 3 hours. This exposure-response disconnect is an important observation for future inhaled drug design strategies considering low solubility to drive lung retention.
Assuntos
Indazóis/farmacologia , Indazóis/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/farmacocinética , Pesquisa Translacional Biomédica , Administração por Inalação , Adulto , Animais , Lavagem Broncoalveolar , Eosinofilia/tratamento farmacológico , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Pulmão/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Permeabilidade , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Segurança , Solubilidade , Escarro/efeitos dos fármacos , Escarro/metabolismo , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversosRESUMO
Nemiralisib (GSK2269557), a potent inhaled inhibitor of phosphoinositide 3-kinase δ (PI3Kδ), is being developed for the treatment of respiratory disorders including chronic obstructive pulmonary disease. Determining the pharmacokinetic (PK) and pharmacodynamic (PD) responses of inhaled drugs early during drug development is key to informing the appropriate dose and preferred dose regimen in patients. We set out to measure PD changes in induced sputum in combination with drug concentrations in plasma and bronchoalveolar lavage (BAL) taken from healthy smokers (n = 56) treated for up to 14 days with increasing doses of inhaled nemiralisib (0.1-6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-(4,5)-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% confidence interval [CI], 11%-34%) and 36% (90% CI, 11%-64%) after a single dose or after 14 days of treatment with nemiralisib, respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of â¼3- to 4.5-fold (peak vs. trough) in plasma exposure after 14 days of nemiralisib treatment. The BAL analysis at trough confirmed higher levels of the drug in the lungs versus plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). A comparison of the drug levels in plasma and the reductions in sputum PIP3 showed a direct relationship between exposure and PIP3 reduction. These results demonstrated target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen.
Assuntos
Voluntários Saudáveis , Indazóis/farmacologia , Indazóis/farmacocinética , Indóis/farmacologia , Indóis/farmacocinética , Oxazóis/farmacologia , Oxazóis/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Piperazinas/farmacologia , Piperazinas/farmacocinética , Fumantes , Adulto , Líquido da Lavagem Broncoalveolar/química , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis/sangue , Indóis/sangue , Masculino , Pessoa de Meia-Idade , Oxazóis/sangue , Fosfatidilinositóis/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/sangue , Piperazinas/sangue , Escarro/efeitos dos fármacos , Escarro/metabolismoRESUMO
Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase involved in leukocyte recruitment and activation. Activation of PI3Kδ has been linked to airway inflammation and asthma pathogenesis. This randomized, double-blind, placebo-controlled, crossover study investigated the efficacy, safety, tolerability, and pharmacokinetics of a PI3Kδ inhibitor, nemiralisib (GSK2269557), in patients with persistent, uncontrolled asthma. Patients (n = 50) received once-daily inhaled nemiralisib (1000 µg) or placebo for 28 days, with a crossover to the alternative treatment following a 4-week washout period. Spirometry demonstrated no discernible difference in trough forced expiratory volume in 1 second (FEV1) from baseline (adjusted posterior median 7 ml; 95% credible interval -83, 102 ml) between nemiralisib and placebo treatment at day 28 (primary endpoint). These results were supported by most secondary endpoints, including weighted mean FEV1 (0-4 hours) and change in trough forced vital capacity at day 28. Nemiralisib was generally well-tolerated, with few side effects except for post-inhalation cough (nemiralisib: 35%; placebo: 9%). At day 14, sputum interleukin (IL)-5, IL-13, IL-6, and IL-8 levels were reduced by a median of 17%, 7%, 15%, and 8%, respectively, when comparing nemiralisib with placebo [n = 15 (IL-5, IL-8) or 16 (IL-6, IL-13); posterior probability of a true ratio >0%: 78%, 64%, 76%, and 63%, respectively]. These results suggest that nemiralisib inhibited PI3Kδ locally; however, this did not translate into meaningful clinical improvement. Further studies will investigate the potential efficacy of nemiralisib in patients with asthma with other specific more severe phenotypes, including those who are colonized with bacteria and frequently exacerbate.
Assuntos
Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Indazóis/administração & dosagem , Indóis/administração & dosagem , Oxazóis/administração & dosagem , Piperazinas/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Adulto , Idoso , Asma/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Capacidade Vital/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: While current therapies reduce symptoms in chronic obstructive pulmonary disease (COPD) patients, substantial unmet need remains and novel treatments are highly desired. Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase specifically expressed in leucocytes and involved in their recruitment and activation. This study evaluated the safety, pharmacokinetics (PK) and dose-response characteristics of inhaled GSK2269557, a PI3Kδ inhibitor, in moderate-to-severe COPD patients with stable disease. METHODS: In this randomised, double-blind, placebo controlled, parallel group study, patients received once daily inhaled treatment with GSK2269557 1000 µg or placebo for 14 days (Part A, primary aim safety, N = 28 patients). In part B of the study (primary aim pharmacodynamic dose-response, N = 36 patients), GSK2269557 100, 200, 500, 700, 1000, 2000 µg or placebo was given for 14 days. In both Part A and B, GSK2269557 was added to the usual maintenance therapy. Safety, PK assessments and induced sputum collection for cytokine analysis were conducted at baseline and after 7 and 14 days of treatment. Adverse events (AEs) were monitored throughout. RESULTS: In Part A, mean age was 61.7 years (SD 6.7), 29% were females, and mean FEV1% predicted was 59.7% (SD 11.4)2. In Part B, mean age was 63.3 years (SD 6.3), 44% were females, and mean FEV1% predicted was 56.5% (SD 11.5)2. GSK2269557 was well tolerated in both parts of the study; the most commonly reported AEs were cough and headache, with cough being reported with a greater incidence in the GSK2269557 groups vs. placebo (Part A: 19% vs. 14% and Part B: range of 0-80% for different doses vs. 0% on placebo). No drug-related serious AEs or clinically significant changes in any other safety parameters were reported. GSK2269557 was rapidly absorbed into plasma following all doses with a maximum peak at approximately 2 h. Following repeat administration, accumulation in plasma was approximately 2-3 fold from Day 1 to Day 7. At Day 14, relative to placebo, sputum interleukin (IL)-8 and IL-6 levels were reduced on average by 32% and 29% respectively after inhalation of GSK2269557 1000 µg in Part A. In Part B, although inhibition of both IL-8 and IL-6 levels was observed, the levels were variable and there was insufficient evidence to support a monotonic dose-response. CONCLUSIONS: In this study, inhaled GSK2269557 had an acceptable safety profile for progression into larger studies in COPD patients. Moreover, inhalation of GSK2269557 resulted in suppression of sputum IL-8 and IL-6 levels, consistent with the known anti-inflammatory activity of a PI3Kδ inhibitor. Inhibition of inflammatory cytokines in the airway compartment may contribute to the potential therapeutic benefit of a PI3Kδ inhibitor in chronically inflamed COPD patients.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Citocinas/metabolismo , Indazóis/administração & dosagem , Oxazóis/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Indazóis/efeitos adversos , Indazóis/farmacocinética , Indóis , Masculino , Pessoa de Meia-Idade , Oxazóis/efeitos adversos , Oxazóis/farmacocinética , Piperazinas , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de Doença , Escarro/metabolismo , Resultado do TratamentoRESUMO
Purpose: This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD). Methods: In this double-blind, placebo-controlled study, 126 patients (40-80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV1) ≤80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734). Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (-1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was >0% (Pr(θ>0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV1 (change from baseline, 95% Cr I (-2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%). Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV1. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.
Assuntos
Fosfatidilinositol 3-Quinases , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Teorema de Bayes , Broncodilatadores/uso terapêutico , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Fosfatidilinositol 3-Quinases/farmacologia , Fosfatidilinositol 3-Quinases/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Resultado do TratamentoRESUMO
Background: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD). Objective: To develop novel, induced sputum endpoints to demonstrate changes in neutrophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3Kδ inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD. Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry. Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals -46, 315mL) with a probability that the true treatment ratio was >0% (Pr(θ>0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged. Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.
Assuntos
Fosfatidilinositol 3-Quinases , Doença Pulmonar Obstrutiva Crônica , Progressão da Doença , Volume Expiratório Forçado , Humanos , Fosfatidilinositol 3-Quinase , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , EscarroRESUMO
Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Sulfonamidas/farmacologia , Animais , Cristalografia por Raios X , Feminino , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Ligação Proteica , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismoRESUMO
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Compostos Heterocíclicos/química , Inibidores de Fosfodiesterase/química , Pirazóis/química , Piridinas/química , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Modelos Químicos , Modelos Moleculares , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Animais , Ligação Competitiva , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Isoenzimas , Modelos Moleculares , Simulação de Acoplamento Molecular , Inibidores de Fosfoinositídeo-3 Quinase/toxicidade , Ratos , Relação Estrutura-AtividadeRESUMO
There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.
Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Antineoplásicos/farmacologia , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Descoberta de Drogas , Feminino , Células HEK293 , Humanos , Masculino , Camundongos SCID , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.
Assuntos
Química Farmacêutica/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Inibidores da Fosfodiesterase 4 , Pirazóis/síntese química , Pirazóis/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Benzamidas/farmacologia , Cristalografia por Raios X/métodos , Ciclopropanos/farmacologia , Desenho de Fármacos , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Modelos Biológicos , Modelos Químicos , Pirrolidinonas/química , Ratos , Rolipram/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability. METHODS: This single-center, 3-part, placebo-controlled trial in 22 healthy subjects evaluated single (100 and 200 µg) and repeat (200 µg for 10 days) doses of inhaled nemiralisib in parts A (nâ¯=â¯12) and B (nâ¯=â¯12) (double-blind) and single doses of inhaled nemiralisib (200 µg) with and without charcoal block in Part C (nâ¯=â¯6) (open-label, 2-period, crossover). There was a minimum 14-day washout period between dosing days. FINDINGS: 21 subjects completed the study, mean age was similar in the three parts (A: 49 years; B: 44 years; C: 55 years). After single doses of nemiralisib, observed plasma Cmax dropped rapidly, followed by a slower elimination phase. Near-dose proportionality was observed: mean (95% CI) plasma Cmax and AUC0-24 values were 174.3 pg/mL (96.9-313.3) and 694.6 pg·h/mL (503.5-958.2) for 100 µg and 398.9 pg/mL (318.3-500.1) and 1699.6 pg·h/mL (1273.3-2268.7) for 200 µg, respectively. Repeat dosing for 10 days showed exposures â¼2- to 4-fold higher than on the single dose (peak, trough, and AUC0-24 levels), achieving steady-state by day 6. Mean AUC0-24 was 2193.6 pg·h/mL and 1645.3 pg·h/mL in the absence/presence of charcoal. Two non-drug-related adverse events were observed; neither was serious or resulted in withdrawal. IMPLICATIONS: Inhalation of nemiralisib was well tolerated in these healthy subjects. Plasma pharmacokinetic variables were well defined, and charcoal block data indicate that â¼23% of the total systemic exposure after inhalation from Ellipta was attributable to orally absorbed drug. ClinicalTrials.gov identifier: NCT02691325.
Assuntos
Indazóis/farmacologia , Indóis/farmacologia , Oxazóis/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Administração por Inalação , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Método Duplo-Cego , Inaladores de Pó Seco , Feminino , Voluntários Saudáveis , Humanos , Indazóis/sangue , Indóis/sangue , Masculino , Pessoa de Meia-Idade , Oxazóis/sangue , Inibidores de Fosfoinositídeo-3 Quinase , Piperazinas/sangue , Inibidores de Proteínas Quinases/sangueRESUMO
A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-Atividade , Administração por Inalação , Animais , Classe Ia de Fosfatidilinositol 3-Quinase/química , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/administração & dosagem , Ligação de Hidrogênio , Isoquinolinas/química , Células Madin Darby de Rim Canino , RatosRESUMO
Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world-wide. Antibody-mediated immune responses can confer protection against repeated exposure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19+B220- B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased susceptibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target.
Assuntos
Linfócitos B/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Infecções Pneumocócicas/imunologia , Animais , Antígenos CD19/metabolismo , Linfócitos B/citologia , Classe I de Fosfatidilinositol 3-Quinases , Ativação Enzimática , Feminino , Técnicas de Introdução de Genes , Genótipo , Humanos , Interleucina-10/metabolismo , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Transdução de Sinais , Especificidade da Espécie , Streptococcus pneumoniaeRESUMO
Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.
Assuntos
Anticoagulantes/síntese química , Inibidores do Fator Xa , Fator Xa/química , Morfolinas/síntese química , Pirrolidinas/síntese química , Sulfonamidas/síntese química , Animais , Anticoagulantes/química , Anticoagulantes/farmacologia , Cristalografia por Raios X , Cães , Feminino , Humanos , Ligantes , Masculino , Modelos Moleculares , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacologia , Ligação Proteica , Tempo de Protrombina , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Albumina Sérica/química , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
The synthesis, antiviral and pharmacokinetic properties of zanamivir (ZMV) dimers 8 and 13 are described. The compounds are highly potent neuraminidase (NA) inhibitors which, along with dimer 3, are being investigated as potential second generation inhaled therapies both for the treatment of influenza and for prophylactic use. They show outstanding activity in a 1 week mouse influenza prophylaxis assay, and compared with ZMV, high concentrations of 8 and 13 are found in rat lung tissue after 1 week. Retention of compounds in rat lung tissue correlated both with molecular weight (excluding 3 and 15) and with a capacity factor K' derived from immobilized artificial membrane (IAM) chromatography (including 3 and 15). Pharmacokinetic parameters for 3, 8 and 13 in rats show the compounds have short to moderate plasma half-lives, low clearances and low volumes of distribution. Dimer 3 shows NA inhibitory activity against N1 viruses including the recent highly pathogenic H5N1 A/Chicken/Vietnam/8/2004. In plaque reduction assays, 3, 8 and 13 show good to outstanding potency against a panel of nine flu A and B virus strains. Consistent with its shorter and more rigid linking group, dimer 8 has been successfully crystallized.
Assuntos
Antivirais/síntese química , Virus da Influenza A Subtipo H5N1 , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Infecções por Orthomyxoviridae/prevenção & controle , Ácidos Siálicos/química , Ácidos Siálicos/síntese química , Animais , Antivirais/química , Antivirais/farmacocinética , Antivirais/farmacologia , Linhagem Celular , Cristalização , Dimerização , Guanidinas , Vírus da Influenza A/enzimologia , Vírus da Influenza B/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/virologia , Masculino , Membranas Artificiais , Camundongos , Modelos Moleculares , Peso Molecular , Infecções por Orthomyxoviridae/virologia , Piranos , Ratos , Ratos Sprague-Dawley , Ácidos Siálicos/farmacocinética , Ácidos Siálicos/farmacologia , Estereoisomerismo , Ensaio de Placa Viral , ZanamivirRESUMO
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
Assuntos
Indazóis/química , Oxazóis/química , Inibidores de Fosfoinositídeo-3 Quinase , Doenças Respiratórias/tratamento farmacológico , Sulfonamidas/química , Administração por Inalação , Animais , Asma/tratamento farmacológico , Feminino , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Indóis , Isoenzimas/antagonistas & inibidores , Masculino , Microssomos/metabolismo , Simulação de Acoplamento Molecular , Ovalbumina/imunologia , Oxazóis/farmacocinética , Oxazóis/farmacologia , Piperazinas , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Coelhos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Células Th2/imunologiaRESUMO
Development of the genital and urinary systems is interwoven. Developmental abnormalities may cause problems in both systems, although the presenting problem may be ambiguous genitalia, hypospadias, undescended testis, or a urinary tract infection. The primary care physician must understand the underlying significance of pediatric urologic problems and seek appropriate consultation in a timely manner.
Assuntos
Doenças Urológicas/terapia , Criança , Criptorquidismo/terapia , Transtornos do Desenvolvimento Sexual/terapia , Emergências , Feminino , Humanos , Hipospadia/terapia , Lactente , Masculino , Médicos de Família , Encaminhamento e Consulta , Infecções Urinárias/terapiaRESUMO
Breast cancer strikes 1 in 10 women in the United States. Early diagnosis of breast cancer improves chances of survival. With universal screening and expert evaluation of early clinical signs and symptoms of breast cancer, mortality rates can be reduced by 30% to 40%. Physicians can help achieve this goal by taking an active role in patient education and promoting the availability of affordable screening mammography.